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Department of Surgery
Vienna Medical School
Austrian Breast & Colorectal Cancer Study Group
The antioestrogen tamoxifen has been available for over 20 years and remains the most commonly recognised endocrine therapy for early breast cancer. Yet, although five years of adjuvant tamoxifen postsurgery has a significant impact on patient outcome, third-generation aromatase inhibitors (AIs) are now challenging tamoxifen as the gold-standard adjuvant hormonal treatment. These drugs are rapidly becoming the first choice for postmenopausal women with hormone receptor-positive breast cancer.
AIs markedly suppress endogenous oestrogens without directly interacting with oestrogen receptors, and thus have a different mechanism of action to tamoxifen. In advanced disease, the nonsteroidal competitive inhibitors anastrozole and letrozole, as well as the steroidal, irreversibly binding inhibitor exemestane, have already been shown to be clinically more efficient and tolerable in the first-line setting.
However, the optimal adjuvant endocrine strategy for early breast cancer in postmenopausal patients remains unclear. The three treatment strategies currently under investigation are:
Early substitution treatment
Results from early adjuvant studies have indicated that AIs may offer greater protection against recurrence than tamoxifen in upfront, head-to-head substitution strategies.
The international, three-arm Arimidex, Tamoxifen, Alone or in Combination (ATAC) study has shown anastrozole to be more effective in terms of disease-free survival (DFS), with important tolerability benefits.(1) Completed analysis of the ATAC trial (n=9,366) at 68 months’ follow-up demonstrated that anastrozole as initial therapy significantly improved DFS (hazard ratio [HR] 0.87, p=0.01) and time to relapse (HR 0.79, p<0.001). This drug also significantly reduced the incidence of distant metastasis (HR 0.86, p=0.04) and contra‑lateral breast cancer by 42% (p=0.01). The anastrozole safety profile in the ATAC trial remains consistent with longer follow-up.
Breast International Group Trial 01.98 (BIG 01.98) is a double-blind, double-dummy investigation comparing letrozole and tamoxifen, with DFS as primary endpoint, in a total of 8,010 women.(2) In addition to its monotherapy arms, this trial is also assessing early sequential adjuvant therapy in two crossover arms (n=1,530). Initial results on the monotherapy arms at a median follow-up of 25.8 months revealed DFS rates of 91.2% vs 89.2% in favour of letrozole (p=0.004).
The ongoing UK Tamoxifen–Exemestane Adjuvant Multicentre (TEAM) trial has recently completed recruitment of some 4,400 patients. The primary objective of this open-label study is to determine whether five years of exemestane improves DFS compared with tamoxifen. Triggered by recent international results from studies in sequential treatment, the TEAM trial is now being amended to effect a treatment changeover, as described below.
Early sequential treatment
A second important strategy, consisting of switching treatment to an AI after two to three years of tamoxifen, has been shown to offer greater protection against disease relapse than tamoxifen alone. The objective of the double-blind Intergroup Exemestane Study (IES) was to compare tamoxifen with the sequential use of tamoxifen and exemestane for a total of five years of treatment (n=4,742). (3) At a median follow-up of 30.6 months, this trial showed that changeover to exemestane after only two to three years of tamoxifen significantly improved DFS (HR 0.68, p<0.001). Overall, this AI was well tolerated compared with tamoxifen.
The Italian Tamoxifen–Anastrozole (ITA) trial compared tamoxifen for five years and two to three years of tamoxifen followed by anastrozole for a total of five years of treatment.(4) Apart from its small size (n=426) and little number of events, time on tamoxifen prior to switching was unfortunately highly variable. At 36 months’ median follow-up, the hazard of recurrence was significantly lower in the sequential arm (HR 0.36, p=0.006).
A recent report of an analysis (n=3,224) combining data from Austrian Breast & Colorectal Cancer Study Group Trial 8 (ABCSG 8) and the German Arimidex–Nolvadex (ARNO) study has demonstrated that anastrozole is beneficial in women who have already received two years of tamoxifen.(5) The primary endpoint was event-free survival (EFS). At a median follow-up of 28 months, we observed a 40% decrease in the risk for an event in the anastrozole group (HR 0.60, p=0.0009). Both treatments were well tolerated.
The primary objective of the Canadian, double-blind, placebo-controlled MA.(17) trial was to determine whether using letrozole as extended adjuvant therapy following five years of tamoxifen would further improve DFS (n=5,187).(6) At 2.4 years median follow-up, estimated four-year DFS was significantly higher in the letrozole arm (p<0.001). The benefit of this AI in significantly reducing the risk of recurrence by 40% (p=0.003) in node-positive and by 53% (p=0.005) in node-negative patients far exceeded the expected difference and the prospectively determined stopping boundary, thus prompting trial unblinding.
The Austrian ABCSG 6a trial was designed to investigate whether continuing endocrine treatment with anastrozole will improve overall prognosis (n=856).(7) Patients who had received five years of tamoxifen alone or in combination with amino‑glutethimide were re-randomised to switch to anastrozole or no treatment for a further three years. The primary endpoint was EFS. At a median follow-up of five years, significantly fewer patients on anastrozole experienced disease relapse (HR 0.64, p=0.047). The results of ABCSG 6a demonstrate the benefit of extended adjuvant treatment with anastrozole. This is being further examined in the framework of the ongoing ABCSG 16 investigation.
In general, there now appears to be a lack of cross-resistance between the classes of AIs, enabling them to be used sequentially and, potentially, to prolong endocrine therapy. An understanding of the resistance mechanisms to these agents is therefore paramount for the appropriate delivery of treatment to responsive patients.
While safety implications of treatment with third-generation AIs for five years or more are being closely monitored, the introduction of these agents has clearly caused a paradigm shift in adjuvant endocrine breast cancer treatment. Anticipated effects of oestrogen deprivation on bone health may prove treatable with bisphosphonates, and this strategy is under investigation.
Overall, current evidence indicates that AIs will greatly enhance survival for many women with early breast cancer, with results still to be verified with respect to benefits in overall survival.