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.     

阿那曲唑对绝经后乳腺癌术前新辅助治疗的临床研究

目的观察阿那曲唑对绝经后乳腺癌术前新辅助治疗的临床应用效果。方法选择符合标准的患者在外科手术前12周开始分别接受阿那曲唑1mg 1mg·d^-1及他莫昔芬20mg·d^-1,于治疗前、治疗后每4周及外科手术前分别对所有患者记录基线测量（二维、使用测量器）和乳腺B超测量（二维）结果并采集血标本检测血雌二醇水平及各项生化指标。结果阿那曲唑组可评价疗效31例,CR0例,PR 11例。总有效率35．5％。SD17例。PD3例。占9．8％。他莫昔芬组可评价疗效27例,CR0例。PR8例,总有效率29．6％．SD14例,PD5例．占18．5％。所有患者辅助治疗结束后均可予行改良根治术。E2的平均抑制率两组分别为77．6％和76．6％。所有病例药物耐受均较好,不良反应轻微。结论阿那曲唑用于绝经后乳腺癌术前新辅助治疗疗效明显．不良反应轻微、耐受良好;且疗效和耐受性均稍好于他莫昔芬。     

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.     

Extended adjuvant endocrine therapy of early breast cancer

ABSTRACT

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.     

Focus on anastrozole and breast cancer

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.     

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.     

Never too late: reducing late breast cancer relapse risk

ABSTRACT

Background: Breast cancer is the most common cancer diagnosed in Europe, with an estimated 429 900 new cases diagnosed in 2006. For over 20 years, tamoxifen was the standard adjuvant (postoperative) endocrine treatment for hormone receptor-positive (i.e., endocrine-responsive) early breast cancer. Yet, even after the first 5 years, patients with hormone receptor-positive tumours are at risk of relapse. Particularly in endocrine-responsive disease, most instances of relapse and breast cancer mortality occur after the first 5 years.

Scope: Extended adjuvant aromatase inhibitor therapy (EAT) now offers postmenopausal women the opportunity to further protect themselves against late relapse.

Methods: This review summarises the clinical evidence and gives practical recommendations for discussing EAT with patients. Relevant information on patients receiving extended or late extended adjuvant endocrine therapy was obtained from databases and congress websites. The most substantial evidence for EAT is provided by the MA.17 trial using letrozole, with similar results obtained from smaller studies using anastrozole or exemestane.

Findings: Extended adjuvant letrozole reduced the risk of recurrence by 42% and the risk of distant metastases by 40%, it was well tolerated compared to placebo; among lymph node-positive patients, overall survival was significantly improved. Ideally, EAT should be started within 3 months of finishing tamoxifen therapy, and evidence supports its use for at least 4 years, showing increasing benefit with longer treatment duration. It is also effective, even after a longer time period, following completion of tamoxifen therapy. When deciding whether or not to use EAT after tamoxifen, clinicians and patients should consider the residual risk of relapse, comorbidities and individual preferences.     

艾愈胶囊联合阿那曲唑治疗绝经后激素受体阳性乳腺癌的临床研究

目的 探讨艾愈胶囊联合阿那曲唑治疗绝经后激素受体(HR)阳性乳腺癌的临床疗效。方法 选取2019年1月-2022年1月海南医学院第一附属医院收治的136例绝经后HR阳性乳腺癌患者,按随机数字表法分为对照组和治疗组,每组各68例。对照组口服阿那曲唑片,1片/次,1次/d。治疗组在对照组基础上口服艾愈胶囊,3粒/次,3次/d。两组均连续治疗3个月。观察两组临床疗效,比较治疗前后两组癌灶最大径、中医症状评分、癌症治疗性功能评价量表-乳腺癌(FACT-B)评分以及血清肿瘤标志物[糖类抗原15-3(CA15-3)、癌胚抗原(CEA)、组织多肽特异性抗原(TPS)]和肿瘤坏死因子(TNF)-α、白细胞介素(IL)-8、血管内皮生长因子(VEGF)、可溶性E-选择素(sE-selectin)水平。结果 治疗后,治疗组客观缓解率是38.2%,高于对照组的29.4%,两组比较差异无统计学意义;治疗组临床获益率是76.5%,显著高于对照组的60.3%(P<0.05)。治疗后,两组癌灶最大径均显著缩小,中医症状评分均显著降低,FACT-B评分则均显著增加(P<0.05);且均以治疗组改善更显著(P<0.05)。治疗后,两组血清CA15-3、CEA、TPS水平均较治疗前显著下降(P<0.05);且均以治疗组降低更显著(P<0.05)。治疗后,两组血清TNF-α、IL-8、VEGF、sE-selectin水平均较治疗前显著下降(P<0.05);且均以治疗组降低均更显著(P<0.05)。结论 艾愈胶囊联合阿那曲唑治疗绝经后HR阳性乳腺癌的抗肿瘤疗效确切,能有效降低患者肿瘤负荷,减轻症状,提高生活质量,并可进一步改善肿瘤微环境,且安全性好。     

New agents for the management of resistant metastatic breast cancer

Introduction: Metastatic breast cancer (MBC) is an incurable disease and treatment is directed towards symptom palliation and survival prolongation. Treatment selection in patients is based on tumor biology, age, comorbidities, performance status, tumor burden, and prior treatment history.

Areas covered: This present review summarizes the recent treatment strategies in the management of MBC, highlighting regimens after first-line therapy. Topics discussed include new strategies for endocrine therapy, anti-HER2 therapy, and promising strategies for the management of triple negative breast cancer.

Expert opinion: MBC is a heterogeneous entity and despite recent advances, there is significant room for improvement of treatment beyond first-line therapies. Combination regimens that can maximize clinical efficacy while minimizing toxicities are required. Current investigation approaches in advanced stages of clinical development include immunoconjugates, immune checkpoint blockade, novel cyclin-dependent-kinase inhibitors, and PARP inhibitors for MBC associated with germline BRCA mutations. We recommend that every patient with MBC should be evaluated for clinical trial options.     

Inhibition of aromatase activity by flavonoids

In searching for potent cancer chemopreventive agents from synthetic or natural products, 28 randomly selected flavonoids were screened for inhibitory effects against partially purified aromatase prepared from human placenta. Over 50% of the flavonoids significantly inhibited aromatase activity, with greatest activity being demonstrated with apigenin (IC50: 0.9 microg/mL), chrysin (IC50: 1.1 microg/mL), and hesperetin (IC50: 1.0 microg/mL).     

含表柔比星化疗方案作为乳腺癌术后辅助治疗的疗效观察

目的探讨含表柔比星化疗方案作为乳腺癌术后辅助治疗的疗效。方法对555例接受含表柔比星方案辅助化疗的乳腺癌患者的总生存率(OS)及不良反应进行分析。结果 380例接受5-氟脲嘧碇/表柔比星/环磷酰胺(FEC组)方案、56例接受长春瑞滨/表柔比星(NE组)方案、82例接受紫杉醇/表柔比星(TE组)方案、37例接受紫杉醇/表柔比星/环磷酰胺(TEC组)方案,四种方案的5年生存率分别为83.6%、89.3%、86.7%和91.7%。Ⅲ度以上骨髓抑制、消化道反应及心脏事件发生率:FEC方案组分别为37.0%、24.9%、0.2%,NE方案组分别为34.6%、19.6%、0%,TE方案组分别为38.8%,17.0%,1.2%,TEC方案组分别为37.8%,18.9%,2.7%。结论含表柔比星的四种辅助治疗方案均能延长生存期,毒副作用可耐受。     

路路通酸对乳腺癌MCF-7细胞和宫颈癌C-33A细胞增殖的影响

目的研究路路通酸(BTA)对乳腺癌MCF-7细胞及宫颈癌C-33A细胞增殖的影响。方法采用MTT法检测不同浓度BTA作用不同时间后对MCF-7细胞、C-33A细胞的增殖抑制作用;流式细胞仪检测BTA处理后细胞周期的变化。结果 BTA作用于乳腺癌MCF-7细胞24、48、72 h后的IC50分别为(37.62±1.72)、(27.32±0.99)、(19.19±0.90)μmol/L。BTA作用于宫颈癌C-33A细胞24、48、72 h后的IC50分别为(34.55±0.88)、(27.20±1.03)、(16.74±0.79)μmol/L,BTA对2种细胞增殖有明显抑制作用,且呈浓度时间依赖性(P<0.05),流式结果显示,BTA将MCF-7细胞阻滞在S期,并诱导其凋亡;BTA将C-33A细胞阻滞在G1-S期。结论BTA对乳腺癌MCF-7细胞和宫颈癌C-33A细胞具有较强的增殖抑制作用,其机制与细胞周期阻滞和诱导细胞凋亡有关。     

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.     

Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.     

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.     

Natural modulators of estrogen biosynthesis and function as chemopreventive agents

There is clearly a need for novel breast cancer chemopreventive agents with enhanced potency and specificity with little or no side effects. To this end, several new chemical moieties have been synthesized or isolated from natural sources. In this review, we have described some agents currently in use or under development for treatment or prevention of breast cancer, as well as our own strategies for the discovery of natural product modulators of estrogen biosynthesis and function. In particular, bioassay-guided fractionation of active plant extracts is a unique method for identifying agents with novel mechanisms of action, some of which should be useful for prevention of human cancer. Further, with the advent of combinatorial chemistry and high throughput screening, even greater progress may now be expected with natural product leads.     

紫杉醇联合米托蒽醌治疗难治性晚期乳腺癌的临床研究

目的 评价紫杉醇联合米托蒽醌治疗难治性晚期乳腺癌疗效。方法 １２例晚期乳腺癌患术后复发转移,接受常规方案治疗失败后改用ＴＭｘ方案化疗：第１ｄ紫杉醇１３５ｍｇ／ｍ＾２,静脉滴注４ｈ;第２ｄ米托蒽辊８ｍｇ／ｍ＾２,静脉滴注３０ｍｉｎ。每４周重复疗程。结果 完全缓解（ＣＲ）２例（１６．７％）,部分缓解（ＰＲ）７例５８．３％。毒副反应主要有白细胞下降。结论 ＴＭｘ方案是治疗难治性晚期乳腺癌疗效较高的方案     

Examining factors associated with adherence to hormonal therapy in breast cancer patients

BackgroudBreast cancer is a rampant disease and is highly prevalent among women in the United States. Two out of three breast cancers are hormone receptor positive and hormonal therapies (Tamoxifen and Aromatase Inhibitors) are used to treat this type of breast cancer. However, adherence to these efficacious therapies is relatively low.PurposeThe aim of this study was to identify factors that are associated with adherence to hormonal therapy among breast cancer patients, and the extent to which they influence adherence, by looking at data from a nationally representative database.MethodsA retrospective cross-sectional study was conducted using Medical Expenditure Panel Survey (MEPS) for 2011–2015. Individuals ≥18 years diagnosed with breast cancer utilizing Tamoxifen and Aromatase inhibitors were identified. The Proportion of Days Covered (PDC) adherence measure was used to classify individuals as adherent (PDC≥80%) or non-adherent (PDC<80%). Multivariable logistic regression was used to determine factors associated with adherence to hormonal therapy.ResultsOut of the 354 breast cancer respondents utilizing hormonal therapy, 194 (54.8%) were adherent and 160 (45.20%) were non-adherent. From 2011 through 2015, an increase in the usage of hormonal therapy was observed. Individuals having at least a high school diploma or General Equivalency Diploma (GED) had 2.795 (1.081, 6.941) times the odds of being adherent when compared to those who did not have a high school diploma or GED. Race, insurance status, marital status, poverty level, class of drug (aromatase inhibitor/tamoxifen), age, comorbidities, out-of-pocket costs and region were not significantly associated with adherence to hormonal therapy among breast cancer patients.ConclusionsThis study found an association between an individual's level of education and adherence to hormonal therapy among breast cancer patients. These results can be used to help optimize allocation of resources to promote knowledge designed to increase the adherence of breast cancer patients to hormonal therapy.