Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early breast cancer: Putting safety issues into perspective

Tamoxifen has been the gold standard adjuvant therapy for the treatment of postmenopausal women with hormone-receptor-positive (HR+) early breast cancer for many years. Tamoxifen treatment is limited to 5 years because of the development of de novo and acquired resistance, and an ongoing risk of adverse events, including endometrial cancer, thromboembolic events, and gynecological symptoms with long-term use. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole, and exemestane, are displacing tamoxifen as the first-choice therapy for HR+ early breast cancer, and are now recommended as the preferred therapy by national and international guidelines. Recent randomized trials have demonstrated that the AIs are more effective than tamoxifen in preventing disease recurrence when used in substitution and sequential strategies in the early adjuvant setting, and letrozole has been shown to be more effective than placebo in the extended adjuvant setting (after 5 years of tamoxifen therapy). Trial safety data show that the overall tolerability of AIs is similar to that of tamoxifen, with adverse events being predictably characteristic of estrogen deprivation; however, some important differences in adverse event profiles between tamoxifen and the AIs have been demonstrated. In addition to antiestrogenic effects, tamoxifen acts as an estrogen agonist in some tissues, which can lead to serious side effects not associated with the AIs, which prevent estrogen biosynthesis. A lower incidence of gynecological and thromboembolic events is observed in patients taking AIs, and fewer cases of endometrial cancer are seen compared with tamoxifen. Adverse events that are more frequent with adjuvant AI therapy compared with tamoxifen include arthralgia and myalgia, bone loss, and effects on the cardiovascular system and blood lipids. The effects of AIs on bone are predictable and may be easily managed, where necessary, with bisphosphonates. Studies examining the effects of AIs on the cardiovascular system and lipid profiles, including in the extended adjuvant setting, suggest that these adverse events may be due to the absence of a protective effect of tamoxifen rather than true AI toxicity. Further studies are required to determine the long-term safety of AI therapy in postmenopausal women with HR+ early breast cancer.     

乳腺癌辅助内分泌治疗概况

乳腺癌的内分泌治疗是激素依赖型乳腺癌患者重要的辅助治疗之一,分为手术治疗和非手术治疗,近年来手术及放射去势治疗逐渐被药物治疗替代。雌激素受体和／或孕激素受体阳性,是目前临床应用内分泌治疗的重要指标。绝经前后患者内分泌环境的生理差别决定了用药方式的不同。绝经前患者主要抑制卵巢产生雌激素,而绝经后患者主要抑制芳香化酶的功能。本文旨在对乳腺癌患者内分泌常用药物进行简要介绍,并就他莫西芬及芳香化酶抑制剂进行重点介绍。     

A roundtable discussion of aromatase inhibitors as therapy for breast cancer

This article summarizes the conclusions of a meeting of diverse breast cancer experts who discussed issues, controversies, and new clinical trial results relevant to the use of aromatase inhibitors for treating postmenopausal women with breast cancer. The new generation of aromatase inhibitors (anastrozole, letrozole, exemestane) have largely replaced megestrol acetate as a second-line therapy in postmenopausal women with hormone-responsive advanced breast cancer. In addition, anastrozole and letrozole have been shown to be superior to tamoxifen for first-line therapy. Finally, recent results suggest that anastrozole may be superior to tamoxifen as adjuvant therapy for early stage disease in postmenopausal women with hormone-responsive disease.     

乳腺癌芳香化酶抑制剂治疗期间骨丢失的长期随访结果

目的 评估绝经后激素受体阳性早期乳腺癌患者术后5年芳香化酶抑制剂（aromatase inhibitor,AI）辅助内分泌治疗过程中的骨丢失情况,为骨健康管理提供依据。方法 本研究为前瞻性观察性研究,入组绝经后激素受体阳性早期乳腺癌患者,接受股骨颈、全髋和腰椎L1-L4等部位的双能X线骨密度检测。AI辅助内分泌治疗前进行基线骨密度检查,治疗期间每年检查骨密度1次。分析AI治疗过程中骨密度变化以及骨质疏松发生率。结果 2013年11月至2016年8月共纳入131例患者,中位年龄60岁,中位绝经年龄50岁,AI治疗时间60～100个月。中位随访86个月,AI治疗5年期间患者腰椎、股骨颈、全髋骨密度逐年下降,5年骨密度总下降率分别为6.90%、5.68%、7.14%,其中第1年骨密度下降最快,第2～5年骨密度平稳下降。腰椎骨密度第1年变化率显著高于第2～5年骨密度变化率（P＜0.01）。进一步分层分析显示,基线骨密度、年龄以及体质量指数值未影响患者骨密度下降率。5年间共17例（17%）患者新发骨质疏松,其中15例为基线骨量低下患者,76%出现在腰椎（13/17）,骨折发生率2%（2/100）。结论 绝经后早期乳腺癌患者5年AI辅助内分泌治疗期间骨密度呈持续下降趋势。应加强AI治疗期间的骨健康管理,早期干预减少骨质疏松的发生。     

芳香化酶抑制剂对绝经后乳腺癌患者 骨折的影响

目的探讨芳香化酶抑制剂(aromatase inhibitors,AI)对绝经后乳腺癌患者骨折发生的影响。方法选择接受AI治疗的绝经后乳腺癌患者70例为治疗组,未接受任何内分泌治疗的绝经后乳腺癌患者89例为对照组。收集骨折相关资料,并以5年用药期为界,比较两组患者骨折发生率及风险。同时,在治疗组患者中,分析相关临床风险因素对骨折发生的影响。结果治疗组和对照组患者总骨折发生率分别为12.86%(9/70)和1.12%(1/89),5年用药期间的骨折发生率分别为10.00%(7/70)和1.12%(1/89),5年用药期过后,治疗组8例患者中有2例发生骨折,而对照组19例患者无一例发生骨折。治疗组患者的骨折发生率均高于对照组(P=0.003,0.018,0.026)。治疗组患者总骨折发生风险和5年用药期间的骨折发生风险高于对照组(P=0.008,0.026)。治疗组患者中,个人骨折史和骨折家族史是增加骨折发生的临床风险因素。结论接受AI治疗的绝经后乳腺癌患者的骨折发生率和骨折发生风险明显增加。因此,绝经后乳腺癌患者在使用AI防治乳腺癌时,要全面评估骨折发生的风险,必要时应采取有效的临床干预措施。     

芳香化酶抑制剂新辅助内分泌治疗三苯氧胺耐药的老年性局部晚期乳腺癌的研究

目的探讨芳香抑制剂新辅助内分泌治疗三苯氧胺耐药的老年性局部晚期乳腺癌的临床疗效。方法回顾性分析既往接受三苯氧胺新辅助内分泌治疗失败,后改用芳香化酶抑制剂,且能够评估疗效和记录疾病进展时间的41例老年性局部晚期乳腺癌患者,主要观察终点为临床获益率（Clinical benefit rate,CBR）。结果分别接受阿那曲唑（n=16）、伊西美坦（n=14）和来曲唑（n=11）新辅助内分泌治疗的三组乳腺癌患者的临床病理特征相似（χ2=1.579,P=0.547）,不同的芳香化酶抑制剂均能获得明显改善三苯氧胺治疗失败的老年性局部晚期乳腺癌的治疗效果,其CBR分别为阿那曲唑62.5%,伊西美坦78.57%和来曲唑72.73%,治疗效果相似（χ2=3.787,P=0.327）。结论芳香化酶抑制剂新辅助内分泌治疗三苯氧胺耐药的老年性局部晚期乳腺癌,仍可以获得明显的临床缓解,且不同的芳香化酶抑制剂的CBR相似。     

Surgery is associated with lower morbidity and longer survival in elderly breast cancer patients over 80

As breast cancer is the most frequent cancer in the elderly with a peak incidence of 1 in 10 by the age of 80, it is important to establish optimum therapy in this group. We conducted a case note-based retrospective study of all elderly primary breast cancer patients aged 80 and above between 1992 and 2002. The type of treatment, complications, disease progression, recurrence, and overall survival were recorded. In all 110 patients aged 80 and above were treated for primary breast cancer, with 32 patients having advanced disease. Of these, 62 patients received primary endocrine treatment. 48 patients underwent surgery with 30 patients undergoing mastectomy. At follow-up, 34 patients suffered disease progression in the primary endocrine treatment group and three patients had local recurrence in the surgical group. The Kaplan-Meier analysis revealed significantly better survival in the surgical treatment group when compared with the primary endocrine treatment group, both in the early disease (n = 41; median survival: 71 months; compared to n = 37; median survival: 42 months; p = 0.0002) and the advanced disease (n = 7; median survival: 48 months; compared to n = 25; median survival: 36 months; p = 0.03). Prompt surgery and adjuvant treatment can decrease relapse and improve survival even in patients older than 80 years.     

Window of opportunity treatment in breast cancer

Window of opportunity therapies, which involve short‐term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone‐receptor positive breast cancer, a 2‐week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision‐making regarding treatment options. Changes in short‐term biomarker endpoints such as cell proliferation measured by Ki‐67 can act as surrogate markers of long‐term outcomes. Paired tissues obtained pre‐ and post‐investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.     

Ectopic breast cancer: special treatment considerations in the postmenopausal patient

A 70-year-old woman with congenital bilateral accessory nipples developed a clinical mass and pain in the left accessory breast tissue. Excision revealed a T2 invasive ductal carcinoma with an identifiable in situ component. No masses were present in the normal breast, and 9 years after surgery, radiation therapy, and tamoxifen there has been no recurrence either in the ipsilateral affected accessory or normal breast tissue.     

Neoadjuvant use of endocrine therapy in breast cancer

Neoadjuvant endocrine therapy is becoming increasingly popular as a safe and effective alternative to chemotherapy in selected patients. Large randomized studies have been published comparing tamoxifen with steroidal and nonsteroidal aromatase inhibitors, with favorable results for aromatase inhibitors letrozole, anastrozole, and exemestane. Endocrine therapy can be used in the neoadjuvant setting for conversion of inoperable breast tumors to operable, and from potential mastectomy to breast-conserving surgery. The use of endocrine agents in this setting also provides an opportunity for the study of their biological effects upon tumor.     

芳香化酶与乳腺癌的相关研究

雌激素在乳腺癌的发生发展中起着重要作用。绝经后妇女的雌激素主要由肾上腺分泌的雄激素前体转化而来,芳香化酶是这一转变过程的关键酶、限速酶。因此,深入研究芳香化酶和乳腺癌的关系具有重要的临床意义。现就芳香化酶在乳腺癌组织中的表达、调控及芳香化酶抑制剂在乳腺癌内分泌治疗中的临床进展作一综述。     

The discrepancy between immunocytochemical and biochemical assay of estrogen receptor in breast cancer patients treated by endocrine therapy

Estrogen receptor (ER) expression was investigated by ER-immunocytochemical assay (ICA) and the dextran coated charcoal (DCC) method in 10 recurrent or primary-advanced breast cancer patients treated with endocrine or chmmo-endocrine therapy. In 6 of these 10 patients, ER was examined both before and after treatments by the 2 methods. ER contents measured by the DCC method were found to be decreased after treatments, however, no change in the immunoreactivities of ER-ICA was observed. In the remaining 4 patients, the ER of new lesions refractory to endocrine or chemo-endocrine therapy was examined. ER status was determined as negative in 3 of the 4 patients by the DCC method, whereas by ER-ICA, the proportion of ER stained cells was about 70 per cent, those cells being diffusely distributed in the section. A discrepancy between ER-ICA and the DCC method was thus demonstrated in breast cancer patients treated by endocrine therapy.     

乳腺癌治疗后高骨质疏松患病率及相关因素分析

目的探索乳腺癌治疗后患者的骨质疏松患病率及相关影响因素。方法回顾性分析147例治疗后并已绝经的乳腺癌患者的临床资料,采用双能X线骨密度吸收仪进行骨密度检测(包括腰椎正位L1~4、股骨颈以及全髋的骨密度测定),分析乳腺癌受体不同表达(ER、PR、HER-2)、年龄、体质量指数(bone mass index,BMI)、绝经时间、术后时间、治疗方法对骨质疏松的影响。结果147例乳腺癌患者治疗后的骨质疏松患病率为40.8%;单因素分析显示年龄、BMI、绝经时间、治疗(内分泌治疗+化疗)、术后时间与骨密度减低呈显著相关(P<0.05),多因素Logistic回归分析显示影响治疗后乳腺癌患者骨密度的主要因素是年龄、BMI、术后时间(P<0.05)。结论乳腺癌治疗后患者具有较高的骨质疏松患病率,乳腺癌治疗的多种因素都能够降低骨密度。     

Single arm phase II study of oral vitamin B12 for the treatment of musculoskeletal symptoms associated with aromatase inhibitors in women with early stage breast cancer

Breast cancer patients receiving endocrine therapy with aromatase Inhibitors (AIs) often experience musculoskeletal and joint‐related side effects. The purpose of this study was to evaluate the effect of Vitamin B12 supplements on musculoskeletal symptoms such as pain and arthralgias induced by AIs and to correlate response with serum and inflammatory biomarkers. Upon receiving approval by the Institutional Review Board (IRB), the majority of the patients consented into the study were treated at the Texas Tech Breast Care Center. Included were patients who had a diagnosis of invasive breast cancer (Stages I‐III), and were experiencing significant musculoskeletal symptoms associated to AIs. Only patients with an average pain score ≥ 4, as assessed by the Brief Pain Inventory‐Short Form (BPI‐SF) questionnaire, were included in the study. Participants received 2500 mcg of sublingual vitamin B12 daily for 90 days. Assessments at baseline and at 3 months included: BPI‐SF pain scores, the impact on quality of life determined by Functional Assessment of Cancer Therapy–Endocrine Symptoms (FACT‐ES), and correlative serum markers relative to baseline (a pre‐post study). A total of forty‐one patients were enrolled. Average pain scores were improved by 34% (P < .0001) at 3 months compared to baseline. In addition, a 23% improvement in worst pain was noted (P = .0003). Analysis of the results for the FACT‐ES scoring showed improvement on all scales. No significant adverse events were observed. Decrease in pain score was correlated with increased serum B12 levels. This study suggests that Vitamin B12 reduces pain and improves quality of life for patients taking AIs who experienced AI‐related musculoskeletal symptoms. If confirmed in large randomized prospective trials, Vitamin B12 would be a safe and cost‐effective option for the treatment of AI‐related musculoskeletal symptoms.     

绝经后Luminal B型乳腺癌的内分泌治疗

目的 探讨芳香化酶抑制剂和三苯氧胺对绝经后Luminal B型乳腺癌患者的疗效.方法 收集天津市肿瘤医院2002年7月至2005年3月间733例术后接受辅助内分泌治疗的原发性乳腺癌患者资料,肿瘤性质均经手术切除病理组织学证实.患者均为绝经后且ER阳性,其中501例接受三苯氧胺治疗,232例接受芳香化酶抑制剂治疗.采用免疫组化SP法进行ER、PR、HER2检测.随访时间36～90个月,中位随访时间46个月.结果 芳香化酶抑制剂治疗组Luminal B型乳腺癌患者三年无瘤生存率高于三苯氧胺组(90.6% vs.88.6%,P=0.038).三苯氧胺组亚组分析显示:LN+/HER2+患者三年无瘤生存率低于LN+/HER2-患者(88.2% vs 90.4%,P=0.037);HER2+/PR+患者高于HER2+/PR-患者(90.8% vs.89.5%,P=0.032).芳香化酶抑制剂组内LN(+)和LN(-)亚组中,HER2(+)患者与HER2(-)患者的三年无瘤生存率差异均无统计学意义(P>0.05);而HER2+/PR+组高于HER2+/PR-组(91.9% vs.90.5%,P=0.029).芳香化酶抑制剂组潮热、阴道出血、静脉血栓形成的发生率低,肌肉骨骼疼痛、骨折的发生率则高于三苯氧胺组(P<0.05).结论 芳香化酶抑制剂对绝经后Luminal B型患者疗效好于三苯氧胺,此效果不受患者腋窝淋巴结状态的影响,且耐受性和安全性较好.     

绝经后Luminal B型乳腺癌的内分泌治疗

目的 探讨芳香化酶抑制剂和三苯氧胺对绝经后Luminal B型乳腺癌患者的疗效.方法 收集天津市肿瘤医院2002年7月至2005年3月间733例术后接受辅助内分泌治疗的原发性乳腺癌患者资料,肿瘤性质均经手术切除病理组织学证实.患者均为绝经后且ER阳性,其中501例接受三苯氧胺治疗,232例接受芳香化酶抑制剂治疗.采用免疫组化SP法进行ER、PR、HER2检测.随访时间36～90个月,中位随访时间46个月.结果 芳香化酶抑制剂治疗组Luminal B型乳腺癌患者三年无瘤生存率高于三苯氧胺组(90.6% vs.88.6%,P=0.038).三苯氧胺组亚组分析显示:LN+/HER2+患者三年无瘤生存率低于LN+/HER2-患者(88.2% vs 90.4%,P=0.037);HER2+/PR+患者高于HER2+/PR-患者(90.8% vs.89.5%,P=0.032).芳香化酶抑制剂组内LN(+)和LN(-)亚组中,HER2(+)患者与HER2(-)患者的三年无瘤生存率差异均无统计学意义(P>0.05);而HER2+/PR+组高于HER2+/PR-组(91.9% vs.90.5%,P=0.029).芳香化酶抑制剂组潮热、阴道出血、静脉血栓形成的发生率低,肌肉骨骼疼痛、骨折的发生率则高于三苯氧胺组(P<0.05).结论 芳香化酶抑制剂对绝经后Luminal B型患者疗效好于三苯氧胺,此效果不受患者腋窝淋巴结状态的影响,且耐受性和安全性较好.     

绝经后Luminal B型乳腺癌的内分泌治疗

目的 探讨芳香化酶抑制剂和三苯氧胺对绝经后Luminal B型乳腺癌患者的疗效.方法 收集天津市肿瘤医院2002年7月至2005年3月间733例术后接受辅助内分泌治疗的原发性乳腺癌患者资料,肿瘤性质均经手术切除病理组织学证实.患者均为绝经后且ER阳性,其中501例接受三苯氧胺治疗,232例接受芳香化酶抑制剂治疗.采用免疫组化SP法进行ER、PR、HER2检测.随访时间36～90个月,中位随访时间46个月.结果 芳香化酶抑制剂治疗组Luminal B型乳腺癌患者三年无瘤生存率高于三苯氧胺组(90.6% vs.88.6%,P=0.038).三苯氧胺组亚组分析显示:LN+/HER2+患者三年无瘤生存率低于LN+/HER2-患者(88.2% vs 90.4%,P=0.037);HER2+/PR+患者高于HER2+/PR-患者(90.8% vs.89.5%,P=0.032).芳香化酶抑制剂组内LN(+)和LN(-)亚组中,HER2(+)患者与HER2(-)患者的三年无瘤生存率差异均无统计学意义(P>0.05);而HER2+/PR+组高于HER2+/PR-组(91.9% vs.90.5%,P=0.029).芳香化酶抑制剂组潮热、阴道出血、静脉血栓形成的发生率低,肌肉骨骼疼痛、骨折的发生率则高于三苯氧胺组(P<0.05).结论 芳香化酶抑制剂对绝经后Luminal B型患者疗效好于三苯氧胺,此效果不受患者腋窝淋巴结状态的影响,且耐受性和安全性较好.     

Molecular breast cancer subtypes in premenopausal and postmenopausal African-American women: age-specific prevalence and survival

BACKGROUND: Breast cancer is currently regarded as a heterogeneous disease classified into various molecular subtypes using gene expression analysis. These molecular subtypes include: basal cell-like, Her-2/neu, luminal A, and luminal B. OBJECTIVES: To analyze the prevalence and clinicopathologic associations for molecular breast cancer subtypes in premenopausal and postmenopausal African-American women. DESIGN: A retrospective analysis of all African-American women diagnosed with breast cancer from 1998 to 2005, who had assessable data for ER, PR, and Her-2/neu status. Molecular subtype classification was done based on immunohistochemical surrogates for ER, PR, and Her-2/neu status obtained from Howard University tumor registry for each patient. The molecular subtypes were defined as: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-), and Her-2/neu (ER-, PR-, and HER2+). OUTCOME MEASURES: We analyzed the prevalence of molecular breast cancer subtypes in a population of African-American women and determined their associations with patient demographics and clinicopathologic variables: node status, tumor size, histological grade, p53 mutation status, and breast cancer-specific survival. RESULTS: The luminal A subtype was the most prevalent in our study sample (55.4%) compared with (11.8%) luminal B, (21.2%) basal cell-like, and (11.6%) Her-2/neu subtypes. The molecular subtypes did not differ by menopausal status. However, when stratified into age-specific groups, the basal cell-like subtype (57.1%) was the most prevalent in the age group <35 y compared with luminal A, luminal B, and Her-2/neu subtypes at 25.0%, 14.3%, and 3.6%, respectively. The basal cell-like subtype also showed an age-specific bimodal distribution with a peak in the <35 y and 51 to 65 y age groups. The basal cell-like and the Her-2/neu subtypes showed an increased association with clinicopathologic variables portending a more aggressive clinical course when compared with luminal A subtype. A paradoxical inverse relationship between the expression of p53 and Bcl-2 protooncoprotein was noted in the molecular subtypes. Breast cancer-specific survival differed significantly among the molecular subtypes (P < 0.04), with the basal cell-like and Her-2/neu subtypes having the poorest outcome. CONCLUSIONS: The high prevalence of the basal cell-like subtype in the young premenopausal African-American women aged <35 y could be a contributory factor to the poorer prognosis of breast cancer observed in this cohort of patients.     

Adjuvant endocrine therapy in postmenopausal breast cancer patients

Tamoxifen has been the endocrine agent of choice for adjuvant hormonal therapy for early breast cancer since approval in 1986. Five years of tamoxifen treatment produced a significant reduction in recurrence and death over more than 10 years of follow-up in women with estrogen receptor-positive (ER+) breast cancer. In large randomised trials, the standard of 5 years tamoxifen has been challenged by third-generation aromatase inhibitors (AIs) in the adjuvant setting. This review provides a synopsis of the most recent trial results and a discussion of remaining areas of uncertainties. Although currently tamoxifen still remains a valid option, increasing evidence from the new AI adjuvant trials suggests that optimised adjuvant endocrine treatment should incorporate an AI either as initial or as sequential therapy.