Role of aromatase inhibitors in the upfront adjuvant hormonal therapy of postmenopausal patients with breast cancer (original) (raw)
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Aromatase inhibitors in the treatment of early and advanced breast cancer
Acta Oncologica, 2005
The third generation aromatase inhibitors anastrozole, exemestane, and letrozole have been compared with tamoxifen and other endocrine therapies in several studies in early and advanced breast cancer. These studies are reviewed in this report. Based on the available evidence, the panel recommends that adjuvant treatment with tamoxifen for 5 years should no longer be considered as the sole standard but that a third-generation aromatase inhibitor should be used either alone or in a sequence with tamoxifen in the adjuvant treatment of postmenopausal women with hormone-receptor-positive breast cancer. Third generation aromatase inhibitors may be considered as the first line therapy of hormone-receptor-positive advanced breast cancer in postmenopausal women, and they may also be used for preoperative therapy of breast cancer.
Defining the roles of aromatase inhibitors in the adjuvant treatment of early-stage breast cancer
Clinical breast cancer, 2005
The widespread use of tamoxifen has led to significant improvements in survival for postmenopausal women with early-stage hormone receptor-positive breast cancer; however, approximately 30% of patients die despite receiving tamoxifen as adjuvant treatment. In addition, concerns exist regarding tamoxifen-associated side effects, including endometrial cancer and thromboembolic disease. The development of the third-generation aromatase inhibitors (AIs; anastrozole, exemestane, and letrozole) therefore represented a welcome potential alternative to tamoxifen. Several clinical trials have demonstrated the superiority of AIs over tamoxifen in the adjuvant treatment of postmenopausal women with hormone-sensitive breast cancer, but these trials differ in their design and in the characteristics of their patient populations. This review discusses the different designs of the primary adjuvant, switching, extended adjuvant, and sequencing trials that are investigating the use of AIs in the adju...
International seminars in surgical oncology : ISSO, 2006
There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2-3 years followed by exemestane or anastrozole for 2-3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy wi...
The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum
Annals of Oncology, 2011
The strategy of using estrogen suppression to treat breast cancer led to the development of aromatase inhibitors, including the third-generation nonsteroidal compounds anastrozole and letrozole, and the steroidal compound exemestane. Aromatase inhibitors potently inhibit aromatase activity and also suppress estrogen levels in plasma and tissue. In clinical studies in postmenopausal women with breast cancer, third-generation aromatase inhibitors were shown superior to tamoxifen for the treatment of metastatic disease. Studies of adjuvant therapy with aromatase inhibitors include (i) head-to-head studies of 5 years of the aromatase inhibitor versus 5 years of tamoxifen monotherapy; (ii) sequential therapy of 2-3 years of tamoxifen followed by an aromatase inhibitor (or the opposite sequence) versus 5 years of tamoxifen monotherapy; (iii) extended therapy with an aromatase inhibitor after 5 years of tamoxifen; and (iv) sequential therapy with an aromatase inhibitor versus aromatase inhibitor monotherapy. Recent results from the Arimidex, Tamoxifen, Alone or in Combination and Breast International Group 1-98 trials advocate using an aromatase inhibitor upfront. This article examines the clinical data with aromatase inhibitors, following a brief summary of their pharmacology.
Aromatase inhibitors in the management of early breast cancer
Ejso, 2008
The adjuvant treatment of patients with endocrine-sensitive breast cancer has been dominated for several decades by the gold-standard tamoxifen. Promising results on the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, in advanced disease led to the development of these agents in the treatment of early breast cancer. Recent results consistently show the superiority of these agents over tamoxifen, and the therapeutic strategies of AIs in the adjuvant setting are still being discussed. Various approaches have been evaluated, including the following: 1. upfront 5-year use of an AI instead of tamoxifen for newly diagnosed patients, 2. upfront sequence of tamoxifen followed by an AI (or the inverse) for a total of 5 years, 3. switching to an AI after 2e3 years of tamoxifen for patients presently on tamoxifen (total of 5 years), 4. extended endocrine therapy with an AI after completing 5 years of adjuvant tamoxifen. However, it is unclear whether one of these AI strategies is superior to the other ones. The overall therapeutic index of AIs appears superior to that of tamoxifen, with proven improved efficacy and a better toxicity profile. AIs are less toxic than tamoxifen in terms of thromboembolic disease and gynaecological complications, while musculoskeletal disorders and joint pains are more frequently seen with AIs. This review explores the results of all phase III adjuvant AIs trials available up to December 2007 and is trying to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.
Aromatase inhibitors for treatment of postmenopausal patients with breast cancer
Expert Review of Anticancer Therapy, 2003
The third generation of aromatase inhibitors and inactivators, such as anastrozole (Arimidex ®), letrozole (Femara ®) and exemestane (Aromasin ®), have become available for treatment of postmenopausal breast cancer patients. Several clinical trials have demonstrated that these new drugs can achieve better treatment results than megestrol acetate (Megace ®) and may replace tamoxifen for the first-line hormonal therapy for metastatic breast cancer patients. In fact, these drugs are now used in many hospitals and clinics for patients with metastatic breast cancer who were previously given tamoxifen as adjuvant treatment. However, the primary concern is whether they can be used as first-line agents for adjuvant treatment of primary breast cancer or are suitable for breast cancer prevention in view of possible adverse side effects. Recently, the Arimidex and Tamoxifen Alone or in Combination trial demonstrated the superiority in terms of disease-free survival of anastrozole over tamoxifen in adjuvant use for postmenopausal patients with Stage I and II primary breast cancer. The results of this report indicate the potential of anastrozole as an alternative drug in the adjuvant setting, although the mean follow-up time is so far only 47 months. Additional data regarding survival resulting from comparative trials of letrozole and tamoxifen and of exemestane and tamoxifen are expected to be available in a few years. However, limited information is available regarding adverse events caused by long-term administration of aromatase inhibitors. Longer follow-up is needed to determine the efficacy and safety of these new aromatase inhibitors when used for adjuvant treatment of postmenopausal patients with breast cancer.
Aromatase inhibitors and their future role in post-menopausal women with early breast cancer
British journal of cancer, 1998
Anastrozole is the first aromatase inhibitor to show a significant survival advantage over megestrol acetate in post-menopausal women with advanced breast cancer. The rationale for extending the use of aromatase inhibitors to the treatment of early breast cancer is based on the efficacy observed in the advanced setting, combined with good tolerability and a convenient dosing regimen. Furthermore, oestrogen deprivation by ovarian ablation (similar to oestrogen antagonism with tamoxifen) is already established as an effective adjuvant treatment in premenopausal women with modality breast cancer. Anastrozole produces a profound suppression of plasma oestrogen levels which is greater than that obtained with earlier aromatase inhibitors (formestane, aminoglutethimide) or megestrol acetate. This could account for the differences in clinical efficacy seen between anastrozole and megestrol acetate. In terms of benefits over other endocrine agents, anastrozole causes significantly less weigh...
Long-term safety of aromatase inhibitors in the treatment of breast cancer
Therapeutics and clinical risk management, 2008
Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI), anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects) or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction) class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the th...
Update on the use of aromatase inhibitors in early-stage breast cancer
Breast Cancer Research, 2009
Aromatase inhibitors are currently included in the 'optimal' management of early-stage breast cancer. Uncertainty remains, however, as to the most appropriate treatment strategy, particularly for newly diagnosed women as they seek to trade off the cost, toxicities and efficacy of the treatment options. Recent publications provide conflicting advice on the role of aromatase inhibitors in the treatment of postmenopausal patients with early-stage hormone receptor-positive breast cancer. This review provides updates on the clinical trials of aromatase inhibitors in early breast cancer and tries to provide practical clinical guidance on their optimal use. Uncertainty remains as to the most appropriate treatment strategy, particularly for newly diagnosed women, as they seek to trade off the cost, toxicities and efficacy of the Review ABCSG = Austrian Breast & Colorectal Cancer Study Group; AI = aromatase inhibitor; ARNO = Arimidex-Nolvadex; ASCO = American Society of Clinical Oncology; ATAC = Arimidex, Tamoxifen, Alone or in Combination; BC = breast cancer; BIG = Breast International Group; BMD = bone mineral density; CI = confidence interval; DFS = disease-free survival; DVT = deep vein thrombosis; ER = oestrogen receptor; HER2 = human epidermal growth factor receptor 2; HR = hazard ratio; HRQoL = health-related quality of life; IES = Intergroup Exemestane Study; ITA = Italian Tamoxifen Arimidex; ITT = intention to treat; MI = myocardial infarction; MRI = magnetic resonance imaging; NICE = National Institute for Health and Clinical Evidence; NSABP = National Surgical Adjuvant Breast and Bowel Project; OS = overall survival; PR = progesterone receptor; PTH = parathyroid hormone; RFS = relapse-free survival; SE = standard error; VTE = venous thromboembolic event.
Breast Cancer Research and Treatment, 2010
To undertake a systematic review of three firstline treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC) in post-menopausal women. We searched six databases from inception up to January 2009 for relevant trials regardless of language or publication status. Randomised controlled clinical trials assessing the safety and efficacy of first-line AIs for post-menopausal women with hormone receptor-positive (HR?, i.e. ER? and/or PgR?) with or without ErbB2 (HER2)-positive MBC, who have not received prior therapy for advanced or metastatic disease were included. Where meta-analysis using direct or indirect comparisons was considered unsuitable for some or all of the data, we employed a narrative synthesis method. Four studies (25 papers) met the inclusion criteria. From the available evidence, it was possible to directly compare the three AIs with tamoxifen. In addition, by using a network meta-analysis it was possible to compare the three AIs with each other. Based on direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-toprogression (TTP) (HR = 0.70 (95% CI: 0.60, 0.82)), objective response rate (RR = 0.65 (95% CI: 0.52, 0.82)) and quality-adjusted time without symptoms or toxicity (Q-Twist difference = 1.5; P \ 0.001). Exemestane seemed significantly superior to tamoxifen in terms of objective response rate (RR = 0.68 (95% CI: 0.53, 0.89)). Anastrozole seemed significantly superior to tamoxifen in terms of TTP in one trial (HR = 1.42 (95% CI: 1.15, NR)), but not in the other (HR = 1.01 (95% CI: 0.87, NR)). In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane (OR = 0.61 (95% CI: 0.38, 0.97)); while exemestane was associated with significantly more arthralgia in comparison with tamoxifen (OR = 2.33 (95% CI: 1.07, 5.11)). Anastrozole was associated with significantly more total adverse events (OR = 1.04 (95% CI: 1.00, 1.09)) and hot flushes (OR = 1.39 (95% CI: 1.03, 1.89)) in comparison with tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs with each other in women with postmenopausal, hormone sensitive advanced or MBC showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes overall survival (OS) and progression-free survival (PFS) showed no significant differences between AIs. OS and PFS showed no significant differences between AIs and hence based on these results a class effect for all AIs is possible. However, these results are based on indirect comparisons and a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with appropriate caution. Head-to-head comparisons between letrozole, anastrozole and exemestane in the first-line MBC setting are warranted.