芳香化酶抑制剂治疗乳腺癌的临床研究进展

综述芳香化酶抑制剂治疗乳腺癌的作用机制、常见药物和在乳腺癌内分泌治疗中的临床研究进展。     

第3代芳香化酶抑制剂在乳腺癌治疗中的应用

第3代芳香化酶抑制剂是绝经后雌激素受体(ER)阳性乳腺癌内分泌治疗的新进展，对晚期乳腺癌的一线治疗优于三苯氧胺(TAM)，其用于TAM治疗失败之后二线治疗的地位已经明确。对早期乳腺癌的辅助治疗和新辅助治疗比TAM更有效。芳香化酶抑制剂对绝经后女性的远期效应有待进一步研究。     

第3代芳香化酶抑制剂在乳腺癌治疗中的应用

第3代芳香化酶抑制剂是绝经后雌激素受体(ER)阳性乳腺癌内分泌治疗的新进展,对晚期乳腺癌的一线治疗优于三苯氧胺(TAM),其用于TAM治疗失败之后二线治疗的地位已经明确.对早期乳腺癌的辅助治疗和新辅助治疗比TAM更有效.芳香化酶抑制剂对绝经后女性的远期效应有待进一步研究.     

芳香化酶与乳腺癌

芳香化酶 (Ａｒｏｍａｔａｓｅ)即雌激素合成酶 ,它催化雄激素转化为雌激素 ,是雌激素生物合成中的限速酶。研究表明它属于细胞色素Ｐ4 50家族 ,故又叫芳香化酶细胞色素Ｐ4 50 (ＡｒｏｍａｔａｓｅＣｙｔｏｃｈｒｏｍｅＰ4 50 )。该酶在人体见于卵巢、胎盘、睾丸、脑、乳腺、脂肪组织、骨与皮肤及某些病理组织如乳腺癌组织、子宫内膜肿瘤组织、异位的子宫内膜组织、子宫平滑肌瘤组织 ,正常无病的成年肝、肾上腺和子宫组织没有芳香化酶的表达。研究表明 ,经由芳香化酶催化雄激素转化而来的雌激素不仅作用于生殖系统和生殖行为 ,也影响肿瘤发…     

芳香化酶抑制剂在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近年来乳腺癌治疗中的新热点,芳香化酶抑制剂是其中的一类重要药物.与三苯氧胺相比,新一代芳香化酶抑制剂用于激素受体阳性的绝经后乳腺癌妇女的新辅助治疗具有明显的优势,临床应用前景广阔,但尚有一些治疗相关的问题值得探讨和进一步研究.     

芳香化酶抑制剂治疗乳腺癌研究进展

全文综述了三代芳香化酶抑制剂用于乳腺癌治疗的现状以及最新研究进展。     

绝经后早期乳腺癌芳香化酶抑制剂治疗相关的骨安全管理中国专家共识

绝经后乳腺癌患者与同龄健康女性相比,骨丢失进一步加速,骨折风险升高,使得病残率和死亡率增加。绝经后乳腺癌患者具有骨丢失的多个危险因素,例如化疗和应用芳香化酶抑制剂（ aromatase inhibitor,AI）治疗等。 AI能够明显改善乳腺癌患者的生存率,但同时也降低雌激素水平,因此,会加速患者的骨丢失,增加骨折风险。随着AI在乳腺癌辅助治疗中的广泛应用,以及乳腺癌患者生存期的延长,应用AI的患者骨丢失的管理也越来越重要。来自全国各地乳腺外科、肿瘤内科、骨科、内分泌科和妇科的多学科知名专家组于2013年讨论并起草了《应用芳香化酶抑制剂的绝经后乳腺癌患者骨丢失和骨质疏松的预防诊断和处理共识》。由于全球临床医师和专家对绝经后乳腺癌骨安全（骨丢失、骨质疏松、骨折）问题的重视和认识的不断加深,且2014年底SOFT研究进一步报道了经卵巢抑制的绝经前乳腺癌患者骨安全问题。因此,中国抗癌协会乳腺癌专业委员会于2015年组织乳腺癌骨安全相关多学科的专家共同讨论对2013年《应用芳香化酶抑制剂的绝经后乳腺癌患者骨丢失和骨质疏松的预防诊断和处理共识》进行修订,并更新为《绝经后早期乳腺癌芳香化酶抑制剂治疗相关的骨安全管理中国专家共识》,以规范绝经后早期乳腺癌骨安全的综合管理。     

芳香化酶抑制剂在乳腺癌治疗中的运用

芳香化酶是绝经后雌激素合成过程中的一个限速酶，而且在乳腺癌组织中为高表达，因此芳香化酶抑制剂（AI）可通过对其抑制作用而控制绝经后乳腺癌的发展。现综述AI的分类、发展、在乳腺癌治疗中的作用机制以及在各期乳腺癌治疗中的应用，并着重介绍第3代AI。     

第30届圣·安东尼奥乳腺癌研讨会有关芳香化酶抑制剂的应用报道

第30届圣·安东尼奥国际乳腺癌研讨会于2007年12月13日至12月16日在美国德克萨斯州的圣安东尼奥市举行。这是关于乳腺癌专题的一次国际性盛会。本文仅对此次会议上讨论乳腺癌手术后如何合理应用芳香化酶抑制剂的一次卫星会议做一简要介绍。     

芳香化酶抑制剂在乳腺癌治疗中的运用

芳香化酶是绝经后雌激素合成过程中的一个限速酶,而且在乳腺癌组织中为高表达,因此芳香化酶抑制剂(AI)可通过对其抑制作用而控制绝经后乳腺癌的发展.现综述AI的分类、发展、在乳腺癌治疗中的作用机制以及在各期乳腺癌治疗中的应用,并着重介绍第3代AI.     

Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer

BACKGROUND: Despite the advantages from using aromatase inhibitors (AIs) compared with tamoxifen for early breast cancer, an unexpectedly greater number of grade 3 and 4 cardiovascular events (CVAE) (as defined by National Cancer Institute of Canada-Common Toxicity Criteria [version 2.0] was demonstrated. METHODS: Phase 3 randomized clinical trials (RCTs) comparing AI with tamoxifen in early breast cancer were considered eligible for this review. The event-based risk ratios (RRs) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Finally, absolute differences (ADs) in event rates and the number of patients needed to harm 1 patient (NNH) were determined. RESULTS: Seven eligible RCTs (19,818 patients) reported CVAE results. When considering all RCTs, the AD of the primary endpoint (CVAE) between the 2 arms (0.52%), tamoxifen versus AI, was statistically significant (RR, 1.31; 95% CI, 1.07-1.60; P= .007). This translated into an NNH value of 189 patients; when only third-generation AIs were considered, the difference (0.57%) remained significant (RR, 1.34; 95% CI, 1.09-1.63; P= .0038). Thromboembolic events were significantly more frequent in the tamoxifen arm, regardless of the strategy adopted (RR, 0.53; 95% CI, 0.42-0.65; P< .0001), without significant heterogeneity (P= .21). An AD of 1.17% and an NNH value of 85 patients were observed. CONCLUSIONS: According to the results from this meta-analysis, the risk of grade 3 and 4 CVAEs in patients who were receiving AIs was higher compared with the risk in patients who were receiving tamoxifen, and the difference reached statistical significance. However, the AD was relatively low, and from 160 to 180 patients had to be treated to produce 1 event.     

Current role and safety profile of aromatase inhibitors in early breast cancer

The current adjuvant therapy for breast cancer is in a continous progress; standard therapeutic strategies include the use of chemotherapy, molecular targeted drugs and hormonal agents, according to well-established prognostic and predictive factors. Among the hormonal drugs, for a long period tamoxifen has been the gold standard of adjuvant therapy in postmenopausal women with hormone receptor-positive (HR+) early breast cancer. In the last years an expanding use of aromatase inhibitors occurred in this subset of patients, because the third-generation class of these agents (anastrozole, letrozole and exemestane) showed to be more effective and safe than tamoxifen and are now recommended as the preferred hormonal approach to postmenopausal hormone-sensitive patients, according to national and international guidelines. Treatment choices with these agents include the use of an aromatase inhibitor as an upfront strategy for 5 years, as a sequential approach after 2–3 years of tamoxifen, or as an extended use after the classical 5 years of tamoxifen. The improved efficacy of aromatase inhibitors over tamoxifen has been largely demonstrated in terms of better disease-free survival, reductions in the occurrence of early distant metastasis as well as improvement of overall survival. Moreover, according to the optimal duration of therapy, presently it is not known whether aromatase inhibitor therapy, as tamoxifen, should be limited to 5 years. In terms of safety profile, the side effects of aromatase inhibitors, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. There is strong evidence that aromatase inhibitors are well tolerated, with a lower incidence of gynecological symptoms (vaginal bleeding, discharge and endometrial neoplasia), venous thromboembolic events and hot flushes than tamoxifen. On the other hand, the use of aromatase inhibitors has been associated with loss of bone density, arthralgia, myalgia, and a negative effect on lipid metabolism and cardiovascular risk. More extensive and mature studies are necessary to well establish the safety of aromatase inhibitors when given to patients with breast cancer for a long time.     

Use of aromatase inhibitors in postmenopausal women with advanced breast cancer

Surgeons have been involved in the management of metastatic breast cancer since the technique of ovarian ablation was introduced in 1896. However, as newer hormonal and chemotherapeutic regimens were developed, drug therapy gradually replaced surgery as the preferred treatment for metastatic breast cancer. Thus, management of metastatic breast cancer has largely shifted from surgeons to medical oncologists. Advances in hormonal pharmacology have placed hormonal therapy alongside surgery and radiation therapy as a standard treatment option for women with advanced breast cancer. The purpose of this article is to update surgeons on the current use of hormonal agents for treatment of advanced breast cancer in postmenopausal women, and to review the aromatase inhibitors, a new line of hormonal agents for the treatment of advanced breast cancer. J. Surg. Oncol. 1997;66:215–220. © 1997 Wiley-Liss, Inc.     

Modeling for cost-effective-adjuvant aromatase inhibitor strategies for postmenopausal women with breast cancer.

BACKGROUND: To determine cost-effective (CE) strategies comparing adjuvant upfront aromatase inhibitor (AI) with sequential tamoxifen (TAM) AI in postmenopausal (PM) women with breast cancer (BC). Design: A Markov model was constructed to calculate cumulative costs and quality-adjusted life year (QALY) gains for upfront AI and TAM-AI in a hypothetical cohort of 60-year-old PM women with BC. Costs, utilities and probabilities were derived from the literature. The hazard ratios (HRs) of AI strategies were applied to a baseline cancer recurrence risk (RR) to determine CE strategies at the $50,000/QALY gain threshold. A direct payer perspective is utilized, and costs and benefits were discounted at 3%. RESULTS: Two-way sensitivity analyses are presented to determine CE strategies across a wide range of HRs and in different clinical scenarios including varying RRs (low, average, high and very high). TAM-AI is the preferred CE strategy at low and average RR, while upfront AI is CE at very high RR. The CE strategy in patients with high RR was dependent on the scenario examined. CONCLUSIONS: This model may help health care providers select CE-adjuvant AI strategies in PM women with BC, until further direct evidence is available from randomized clinical trials.     

Aromatase inhibitors in breast cancer therapy

Estrogens are involved in numerous physiological processes and have crucial roles in certain disease states, such as mammary carcinomas. Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in breast tissue and the importance of intratumoral aromatase and local estrogen production is being unraveled. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. Steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy for the treatment of breast cancer. The initial nonselective nature of nonsteroidal inhibitors, such as aminoglutethimide, has been greatly reduced in the later generations of inhibitors, anastrozole and letrozole. Mechanism-based steroidal inhibitors, such as 4-hydroxyandrostenedione and exemestane produce potent aromatase inhibition in patients. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole and exemestane, are approved for clinical use as first-line endocrine therapy in postmenopausal women with metastatic hormone-dependent breast cancer and as second-line endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies.     

Cognitive limitations associated with tamoxifen and aromatase inhibitors in employed breast cancer survivors

Objectives: Previous research has suggested that endocrine therapy is associated with cognitive limitations in breast cancer survivors (BCS); this study examined the relationship in employed BCS, an average of three years post‐primary treatment. Methods: 77 BCS with past or current exposure to tamoxifen or aromatase inhibitors and 56 BCS with no history of endocrine therapy completed self‐report measures of cognitive function, anxiety, depression, and fatigue as well as an online neurocognitive battery. Results: Exposure to endocrine therapy was not related to scores on the objective measures, but moderately related to perceived attentional problems at work (β = ?0.20; CI_0.95 = ?2.75, ?0.25) and perceived cognitive functioning in overall life (β = 0.17; CI_0.95 = 0.33, 11.47) in excess of what could be explained by symptom burden measures. No differences were reported between groups on symptom burden measures. Symptoms of physical fatigue, depression, and anxiety were positively associated with self‐report of general cognitive limitations (R² change range: 0.28–0.37), and symptoms of depression and anxiety were positively associated with perceived cognitive limitations at work (R² change range: 0.21–0.28). Discussion: Symptoms of depression, anxiety, and fatigue should be screened for and treated in BCS, as an approach to mitigating perceived cognitive limitations. However, healthcare providers should be aware that cognitive limitations exist in excess of what can be associated with symptom burden, and may be related to endocrine therapy and other cancer treatments. Copyright © 2010 John Wiley & Sons, Ltd.     

Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer

Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer.     

The breast cancer continuum in hormone-receptor-positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors.

There are now a number of highly effective options for the treatment of hormone-receptor-positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast-conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor-positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node-positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women.