Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women

ABSTRACT

Objective: Third-generation aromatase inhibitors (AIs) are effective and generally well-tolerated as adjuvant therapy. These AIs are now being introduced for the adjuvant treatment of postmenopausal patients with estrogen-receptorpositive early-stage breast cancer. However, questions remain about their long-term safety. This paper summarizes the adverse events reported in third-generation AI trials and comments on the appropriate management of these drug-induced adverse events in patients.

Methods: Papers relating to anastrozole, exemestane, and letrozole were identified through Medline searches, and proceedings of recent oncology meetings were also reviewed to capture relevant emerging data.

Results: The most commonly reported adverse events associated with adjuvant AI therapy include hot flushes and musculoskeletal complaints/arthralgia. The incidence of endometrial cancer and thromboembolic events is significantly lower with an AI than with tamoxifen. However, there is a small but significant increase in the risk of osteoporosis and fractures with AI therapy. A potential negative effect on the cardiovascular system, specifically on lipid metabolism, has not been conclusively demonstrated. No significant differences in overall quality of life were observed in studies comparing AIs with tamoxifen or placebo.

Conclusion: AIs alone and sequenced after tamoxifen are an appropriate option for adjuvant endocrine therapy for most postmenopausal patients with hormone-responsive breast cancer. The incidence of some side effects such as endometrial cancer, stroke, or pulmonary embolism associated with tamoxifen is decreased. Monitoring and management of bone loss associated with AI treatment are essential and are being addressed in ongoing trials. Further studies with longer follow-up are required to clarify the effects of AIs on lipid metabolism and cardiovascular health.     

Initial versus sequential adjuvant aromatase inhibitor therapy: a review of the current data

ABSTRACT

Objective: One of the principle unresolved questions in adjuvant endocrine therapy for breast cancer is whether it is more beneficial for women to receive aromatase inhibitor (AI) monotherapy or start with tamoxifen and then switch to AI therapy. This review will compare the current available efficacy, safety, and cost-effectiveness data for AIs in the initial adjuvant and switch adjuvant settings.

Methods: A search of the Medline database from 1976 through 2006 was performed for the following terms: breast cancer, adjuvant, aromatase inhibitors, anastrozole, letrozole, exemestane, tamoxifen, sequential, switching. A search for relevant abstracts from the EBCC, ECCO, ASCO, and SABCS conferences was also performed.

Results: In the upfront adjuvant setting, anastrozole and letrozole have both demonstrated a significant disease-free survival (DFS) benefit over tamoxifen. Upfront therapy with a non-steroidal AI appears to be most critical for patients at risk of an early relapse, illustrated by the finding that upfront letrozole provided a significant early DFS advantage over tamoxifen only in patients with node-positive disease (hazard ratio = 0.71, p < 0.001). With respect to safety, both strategies have similar adverse event profiles. From an economic perspective, AIs, whether used upfront or sequentially, are considered cost-effective compared with tamoxifen due to the cost savings associated with a reduction in the breast cancer event rate. From the efficacy standpoint, modeling studies have produced inconsistent results and do not produce definitive data.

Conclusions: Differences in patient populations, definitions of end points, and prior tamoxifen usage between the trials discussed necessitates a careful interpretation but may provide insights in the treatment decision-making process. The BIG 1-98 trial was designed to compare letrozole monotherapy versus a letrozole-to-tamoxifen or reverse-sequence approach and should provide insights to the question of optimal therapy. Until results are available, for higher-risk patients (i.e., those with positive lymph nodes), initiation of treatment with a non-steroidal AI may be beneficial to avoid tamoxifen-associated early relapses that occur in the first 2 years after diagnosis.     

Focus on anastrozole and breast cancer

SUMMARY

This commentary article provides an overview of recent clinical research trials involving anastrozole and its evolving role in the management of breast cancer.

Anti-aromatase agents inhibit the cytochrome P-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues which are the main source of estrogen in postmenopausal women. Anastrozole is a third-generation non-steroidal aromatase inhibitor. It has been shown to be superior to megestrol acetate, in terms of survival and adverse effects, as a second-line therapy in postmenopausal women with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer. Phase III clinical trials have also demonstrated that anastrozole significantly prolongs the time to tumour progression compared with tamoxifen as a first-line therapy for ER- and/or PgR-positive advanced breast cancer in postmenopausal women. Furthermore, the preliminary results of the Arimidex, Tamoxifen, Alone and in Combination (ATAC) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), non-musculoskeletal adverse effects and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. Although longer follow-up is required to assess the long-term effects of anastrozole on bone mineral density, cognitive function and overall survival, the drug has been recently approved for adjuvant use in postmenopausal women with early, ER-positive breast cancer who are unable to tolerate tamoxifen or at an increased risk of developing thromboembolism or endometrial cancer.

The potential role of anastrozole in the neoadjuvant setting, the management of DCIS, premenopausal breast cancer and breast cancer prevention is currently being investigated.     

Extended adjuvant endocrine therapy of early breast cancer

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen. This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.     

Assessing the risk of bone fracture among postmenopausal women who are receiving adjuvant hormonal therapy for breast cancer

ABSTRACT

Objective: To understand better the true impact of wide­spread adoption of adjuvant aromatase inhibitor (AI) therapy on postmenopausal breast cancer patients’ risk of bone fracture.

Methods: Data from three different studies were used to estimate the relative risk of bone fracture for each of the following groups of women (i.e., versus a control group of healthy postmenopausal women): (a) healthy postmenopausal women receiving tamoxifen; (b) post­menopausal women who had received treatment for early breast cancer; (c) postmenopausal breast cancer patients on adjuvant tamoxifen therapy; (d) postmenopausal breast cancer patients on adjuvant anastrozole therapy. The results of these analyses were then used to estimate the likely incidence of clinical fracture among such popula­tions in ‘real-life’ clinical practice.

Results: Breast cancer survivors were calculated to be at increased risk of clinical bone fracture (i.e., RR 1.15 vs. control group over 5 years). Breast cancer patients initiated on adjuvant anastrozole were also calculated to be at increased risk of bone fracture (RR = 1.36 vs. control group over 5 years), while the calculated risk of fracture among tamoxifen-treated breast cancer patients was similar to that observed in the control population (RR = 0.91).

Conclusion: Breast cancer patients are at increased risk of clinical bone fracture (compared with the general postmenopausal population) and adjuvant anastrozole therapy slightly adds to this risk. Importantly, however, the absolute risk of bone fracture appears to remain low in each of the evaluated patient populations, suggesting that fear of fracture should not prevent the initiation of adjuvant aromatase inhibitor therapy.     

Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer

ABSTRACT

Background: Over the past few years, data have been published concerning the relative efficacy and safety profiles of tamoxifen and the aromatase inhibitors (AIs) in the adjuvant therapy setting for women with early hormone receptor-positive breast cancer. Recently, debate has centred around trials which have studied primary tamoxifen and AI therapy, switching and equencing strategies and extended adjuvant therapy.

Methods: Here, a group of 24 breast cancer experts review efficacy and safety data from the recent major trials investigating tamoxifen and the third-generation AIs in postmenopausal women, which have challenged the perception of tamoxifen as optimum adjuvant endocrine therapy. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, Breast International Group (BIG) 1‐98 study, National Cancer Institute of Canada MA 17 trial, Intergroup Exemestane Study (IES), Italian Tamoxifen Anastrozole (ITA) trial, Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and Arimidex-Nolvadex (ARNO) 95 are considered to provide a rational interpretation of the impact of these data on current practice, and to highlight areas where further investigation is needed.

Conclusion: We can be confident that AIs represent superior adjuvant endocrine treatment to tamoxifen in postmenopausal women, either as initial therapy or as an alternative for women who have started adjuvant therapy with tamoxifen. However, there remain issues regarding the best way to use AIs, such as the optimal length of AI treatment and how a sequence of tamoxifen followed by an AI compares with AI monotherapy; these will require further data to resolve.     

A clinical perspective on escalating or de-escalating adjuvant therapy in HER2+ breast cancer

Introduction: Patients with early HER2-positive breast cancer (BC) benefit from HER2-targeted systemic therapy. The endorsed standard adjuvant treatment for patients with early HER2-positive breast cancer is chemotherapy plus trastuzumab administered for 1 year.

Areas covered: Several trials have investigated modifications of the standard treatment in terms of de-escalation by either shortening the duration or giving less resource-demanding regimens and in terms of escalation by either adding a second anti-HER2 agent or extending the duration of HER2-targeted treatment for more than 12 months. In this perspective, we would offer a comprehensive view of these trials and discuss their findings.

Expert commentary: At the current state of knowledge, there are still open questions regarding the management of HER2+ BC patients, such as the most adequate duration of trastuzumab therapy, the optimal chemotherapy regimen that should be combined with trastuzumab, and the addition of a second anti-HER2 agent. Growing evidences suggest that some HER2+ BC patients may not need chemotherapy. If these patients could be recognized upfront, optimal response could potentially be reached with HER2-targeted therapy alone.     

Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer

Abstract

Background:

The Breast International Group (BIG) 1-98 and Arimidex, Tamoxifen Alone or in Combination (ATAC) trials demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early-stage breast cancer, 5 years of initial adjuvant endocrine therapy with letrozole or anastrozole is superior to tamoxifen. With expected generic availability of anastrozole in July 2010 and letrozole in June 2011, there may be financial pressures prior to letrozole's generic availability to start treatment-naïve patients on anastrozole vs. letrozole or to switch patients already receiving letrozole to anastrozole.     

芳香化酶抑制剂来曲唑的研究进展

来曲唑是新一代强效的非甾体芳香化酶抑制剂,用于一线治疗晚期乳腺癌,并广泛用作乳腺癌的二线用药．疗效好,不良反应少,耐受性好．值得临床推广应用。本文综述了来曲唑的合成方法以及临床研究进展。     

乳腺癌保乳治疗29例疗效分析

目的 探讨乳腺癌保乳治疗的方法与疗效.方法 对收治的29例早期乳腺癌患者进行保乳手术(保乳组),并辅助放化疗;并于同期36例行改良根治术的乳腺癌患者(对照组)进行比较.结果 与对照组相比,保乳组生存率、复发率无统计学意义(P＞0.05),但生活质量明显提高,保乳治疗术后必须进行放化疗及内分泌治疗,其中1例因未行化疗而复发.结论 早期乳腺癌患者接受保乳综合治疗能取得满意的疗效,值得临床推广.     

不同类型内分泌药物治疗对乳腺癌患者骨代谢的影响

目的 观察不同类型内分泌药物治疗对乳腺癌患者术后骨代谢水平的影响。方法 收集2013年5月至2019年1月南方医科大学附属小榄医院治疗的乳腺癌患者239例,按照内分泌治疗药物不同分为A组（采用他莫昔芬治疗,75例）、B组（采用氟维司群治疗,83例）和C组（采用依西美坦治疗,81例）。比较各组治疗前及治疗12个月降钙素（CT）、骨钙素（BGP）、骨碱性磷酸酶（BAP）和甲状旁腺素（PTH）水平,同时检测各组腰椎骨密度（BMP）并比较。结果 治疗前,三组CT、BGP、BAP、PTH和BMP值比较,差异均无统计学意义（P>0.05）;治疗后,三组CT均不同程度升高,其中C组升幅最大,A组升幅最小,组间差值比较,差异有统计学意义（P=0.009）;三组BGP均不同程度升高,其中A组升幅最大,B组升幅最小,组间差值比较,差异有统计学意义（P=0.005）;三组BAP均不同程度降低,其中B组降幅最大,A组降幅最小,组间差值比较,差异有统计学意义（P=0.018）;三组PTH均不同程度降低,其中C组降幅最大,A组降幅最小,组间差值比较,差异有统计学意义（P=0.025）。治疗后,A组腰椎BMP未见明显降低,但C组腰椎BMP下降较明显,三组间BMP治疗前后差值比较,差异有统计学意义（P=0.022）。结论 不同内分泌治疗药物均可导致乳腺癌患者BMP降低,但他莫昔芬对患者骨代谢水平影响程度较小。     

来曲唑单药治疗ER阳性激素反应性早期乳腺癌的效果及不良反应观察

目的 研究来曲唑单药治疗雌激素受体(ER)阳性激素反应性早期乳腺癌的效果及不良反应.方法 选择2009年2月至2010年2月本院70例早期ER阳性激素反应性乳腺癌患者作为研究对象,随机分为两组,每组35例.观察组行来曲唑单药治疗,对照组行他莫昔芬序贯来曲唑治疗,观察两组治疗效果及不良反应发生情况.结果 观察组近期总有效率为85.71％,对照组为82.86％,差异无统计学意义(P＞0.05).观察组1、3、5年存活率分别为94.29％、90.91％及83.33％,与对照组比较差异无统计学意义(P＞0.05).观察组治疗3年复发率为20.00％,显著低于对照组的46.43％,差异有统计学意义(P＜0.05).观察组高脂血症和关节疼痛发生率显著高于对照组,潮热、阴道出血及静脉血栓发生率显著低于对照组,差异均有统计学意义(P＜0.05).结论 来曲唑单药治疗ER阳性激素反应性早期乳腺癌效果显著,复发率低,临床应用时应充分评估复发风险和不良反应情况,坚持个体化治疗.     

105例乳腺癌辅助内分泌治疗依从性分析

目的 了解乳腺癌辅助内分泌治疗的依从性,分析影响因素,提出对策.方法 回顾性分析2007年1月至12月在汕头市中心医院诊治的105例受体ER和（或）PR阳性的乳腺癌患者随访数据（包括门诊随访、住院随访和电话随访）,运用药物占用比（MPR）及白行设计调查问卷方法,了解辅助内分泌治疗依从性及影响原因.结果 成功随访102例,占97.14％,根据MPR将102例乳腺癌患者分为依从性良好组和依从性不良组,发现疾病认知程度、复查情况、就医环境和经济状况与乳腺癌患者术后内分泌治疗依从性相关.结论 本研究乳腺癌患者辅助内分泌治疗总体依从性偏低.可从加强患者健康教育、定期门诊复查、减轻患者经济负担、定期随访四方面来提高内分泌治疗依从性.     

Exemestane in postmenopausal women with early or advanced breast cancer: a review

Importance of the field: Inhibition of the aromatase enzyme in postmenopausal women reduces levels of estrogens, which is of therapeutic value in hormone-sensitive breast cancer. Exemestane is a third-generation steroidal irreversible inactivator of the aromatase enzyme used in early and advanced breast cancer for the treatment of postmenopausal women with estrogen-receptor-positive disease.

Areas covered in this review: The scientific literature on exemestane, including published articles and abstracts, was searched from 1988 to the present, and the most significant results are included in the review.

What the reader will gain: The review outlines the pharmacological characteristics of exemestane and the evidence supporting its use in the treatment of postmenopausal women with early or advanced estrogen-receptor-positive breast cancer.

Take home message: Exemestane is an effective and well-tolerated aromatase inhibitor with a defined role in early-stage breast cancer following 2 – 3 years of adjuvant treatment with tamoxifen. Exemestane also has a role in the sequence of hormonal agents employed to control advanced hormone-sensitive breast cancer, in which clinicians may exploit its partial lack of cross-resistance with nonsteroidal aromatase inhibitors.     

Use of LHRH-agonists as adjuvant therapy for breast cancer

Individual data was collected for 11,906 women in 16 randomised trials evaluating a luteinising-hormone-releasing hormone (LHRH) agonist either alone, as an addition to tamoxifen or chemotherapy or in place of chemotherapy. When used alone these agents led to a large (28%) relative decrease in recurrence, which was not significant (p = 0.08) due to the small number of patients randomised. Addition of LHRH-agonist to tamoxifen, chemotherapy or both, reduced recurence by 13% (p = 0.02), and when used alone these agents showed similar efficacy to chemotherapy. The largest effect after chemotherapy was seen in women aged ≤ 40 years. Most of the chemotherapy was CMF-based, so comparisons with more modern chemotherapy would be useful. In addition, the optimum duration of treatment is unknown.     

乳腺癌内分泌治疗研究进展

内分泌治疗用于乳腺癌已有100多年的历史,具有疗效确实、耐受性良好的特点,已在各期激素受体阳性乳腺癌的辅助治疗中占据重要地位。目前,三苯氧胺仍是绝经前患者的标准用药,绝经后患者则首选芳香化酶抑制剂。本文就近年来进行的多个大宗临床试验,对乳腺癌内分泌治疗研究进展做一综述。     

辅助化疗、内分泌治疗对绝经后乳腺癌患者骨密度的影响

目的 研究辅助化疗、内分泌治疗对绝经后乳腺癌患者骨密度及骨丢失的影响.方法 收集2013年6月至2015年10月在本院诊断为绝经后乳腺癌患者共50例,分别在患者外科术后、接受常规化疗前及常规化疗完全结束后,内分泌AI治疗1年后,采用双能X线骨密度测量仪测量腰椎L2～L4及右股骨颈的骨密度.比较常规化疗前与常规化疗后,常规化疗后与AI治疗1年后腰椎及股骨颈的骨密度是否存在差异.结果 常规化疗后患者腰椎及股骨颈的骨密度较常规化疗前显著降低,其差异具有统计学意义;AI治疗1年后腰椎和股骨颈的骨密度较常规化疗后的骨密度显著降低,其差异具有统计学意义.结论 辅助化疗及内分泌治疗可不同程度的影响绝经后乳腺癌患者的骨代谢、降低骨密度,早期采用干预措施对预防骨丢失及骨质疏松是非常必要的.     

35例早期乳腺癌保乳手术治疗

目的 探讨早期乳腺癌保乳治疗的适应症及方法。方法 回顾性分析云南省肿瘤医院2002年8月～2005年6月接受了保乳治疗的35例早期乳腺癌资料。35例均行肿瘤扩大切除加腋淋巴结清扫，术后均进行了放疗和化疗。结果 存活时间30个月无局部复发；保留乳房外观满意率为82．8％。结论 早期乳腺癌的保乳手术治疗安全、疗效确切。但必须正确掌握手术指征及规范的广泛切除、腋淋巴结清扫及术后辅助放疗是早期乳腺癌保乳治疗的关键措施，可使局部复发率降低；同时保乳治疗后大多数病例能够保持良好的乳房外形。     

The cost-effectiveness issue of adjuvant trastuzumab in early breast cancer

Trastuzumab has shown activity in patients with early breast cancer that overexpresses HER-2, and this drug has been employed in the adjuvant setting. Significant resources have been allocated to finance this new therapy. To support decision makers in their allocation of resources, cost-effectiveness models are constructed to compare the costs and outcomes of anticancer therapy. This survey focuses on studies exploring adjuvant trastuzumab therapy in early-stage breast cancer that have been published since 2003, which report on efficacy, benefit and/or cost data in this setting. The paper summarises the results, focuses on the level of evidence of these studies, compares the calculated cost-effectiveness ratios and makes recommendations for future cost-effectiveness analyses.