Clinical and Economic Benefits of Aromatase Inhibitor Therapy in Early-stage Breast Cancer

Stefan Glück; Fariborz Gorouhi


Am J Health Syst Pharm. 2011;68(18):1699-1706. 

In This Article

Clinical Benefits of AIs

Using the currently accepted gold standard for clinical efficacy— improvement in disease-free survival rather than overall survival— exemestane, anastrozole, or letrozole as monotherapy or in sequence with tamoxifen has been found to be superior to tamoxifen monotherapy (Table 1).[9,10,11,12,23,24,25,26,27] Since distant metastasis is strongly correlated with the risk of death, it can be argued that reducing distant metastasis as the first recurrent event may result in a survival benefit.


The Intergroup Exemestane Study (IES) investigated whether patients who were disease free after 2 to 3 years of tamoxifen therapy benefited from a switch to exemestane (n = 2362) versus continued therapy with tamoxifen (n = 2380) for the remainder of the 5-year treatment period.[27] At 30.6 months, exemestane improved survival free of distant disease (HR = 0.66, 95% CI, 0.52–0.83, p = 0.0004), though overall survival in the intent-to-treat group was not significantly different. At 55.7 months, only 4724 patients (2352 in the exemestane group and 2372 in the tamoxifen group) were considered evaluable, as the validity of data for 18 patients could not be confirmed.[9] In patients with ER- positive tumors or tumors whose ER status was unknown, a 17% benefit was observed in the exemestane group in time to distant recurrence (HR = 0.83; 95% CI, 0.70–0.98; p = 0.03) and survival (HR = 0.83; 95% CI, 0.69–1.00; p = 0.05). The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial initially randomized women to receive exemestane (n = 5868) or tamoxifen (n = 2898) but was amended to allow patients in the tamoxifen group to switch to exemestane after 2.5–3 years of treatment as a result of the disease-free survival benefits observed in the IES.[23] Rea et al.[13] found no significant difference in distant metastasis as the first recurrent event or overall survival between the study groups at 5.1 years, and it remains to be seen whether an advantage with exemestane alone versus sequential tamoxifen and exemestane will emerge over time in this trial.


In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, 9366 women were randomized to receive tamoxifen, anastrozole, or a combination of the two agents, though the combination group was eventually closed due to the lack of superiority.[25] By 68 months, anastrozole treatment significantly prolonged the time to distant recurrence by 14% (HR = 0.86; 95% CI, 0.74–0.99; p = 0.04) in the intent-to-treat population. Overall survival was similar between the two groups. At 100 months, the time to distant recurrence was prolonged for the anastrozole group in both the intent-to-treat (HR = 0.86; 95% CI, 0.75–0.98; p = 0.022) and the hormone-receptor-positive (HR = 0.84; 95% CI, 0.72–0.97; p = 0.022) populations, though no significant differences in mortality were observed.[10] The Arimidex-Nolvadex 95 (ARNO 95) and Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) trials investigated the benefits of switching to anastrozole after 2 years of tamoxifen treatment.[11] A combined analysis of 3224 patients who were disease free before switching to anastrozole found that at 3 years after switching treatment, the risk of distant metastasis as the first event decreased by 46% (HR = 0.54; 95% CI, 0.37–0.80; p = 0.0016) among women who received sequential therapy compared with those who received tamoxifen mono-therapy. No significant difference in survival was observed. Results of a meta-analysis of the ABCSG 8 trial, ARNO 95 trial, and a similarly designed trial—Italian Tamoxifen Anastrozole (ITA)—revealed that switching to anastrozole resulted in significant improvements in distant recurrence-free survival (HR = 0.61; 95% CI, 0.45–0.83; p = 0.002) and overall survival (HR = 0.71; 95% CI, 0.52–0.98; p = 0.04).[28] The difference in survival outcomes among trials is unclear, though the treatment (monotherapy versus sequential therapy) and patient selection (disease free after tamoxifen) may have affected the outcomes. It is also possible that an overall survival advantage in the ATAC trial will emerge over time, as observed in the IES.


The Breast International Group 1–98 (BIG 1–98) trial enrolled 8028 women who were randomized to receive tamoxifen for 5 years, letrozole for 5 years, or a sequential regimen of tamoxifen or letrozole for 2 years followed by the other agent for 3 years.[26] Analysis at 25.8 months included data from 8010 women from all study groups who had received monotherapy or switched to the alternative agent for no more than 30 days. Results showed that letrozole reduced the risk of recurrence at distant sites by 27% (HR = 0.73; 95% CI, 0.60–0.88; p = 0.001). As a result of the significant disease-free survival benefit also observed in the letrozole-treated group at 25.8 months (HR = 0.81; 95% CI, 0.70–0.93; p = 0.003), 619 (25.2%) of 2459 patients in the tamoxifen group opted to selectively switch their treatment to letrozole.[29] An analysis at 76 months, which included only the 4922 patients randomized to receive continuous adjuvant therapy, demonstrated a significant improvement in time to distant recurrence of 15% in favor of letrozole (HR = 0.85; 95% CI, 0.72–1.00; p = 0.05).[12] A nonsignificant overall survival benefit of 13% (HR = 0.87; 95% CI, 0.75–1.02; p = 0.08) was observed in patients receiving letrozole. To account for potential biases resulting from the significant crossover, a censored analysis and an inverse probability of censoring weighted (IPCW) analysis were undertaken. In the censored analysis, differences in time to distant recurrence (HR = 0.81; 95% CI, 0.68–0.96) and overall survival (HR = 0.81; 95% CI, 0.69–0.94) between letrozole and tamoxifen were increased compared with the intent-to-treat analysis.[12] The IPCW analysis, which corrects for nonadherence, estimated a 19% improvement in time to distant recurrence (HR = 0.81) and a 17% overall survival benefit (HR = 0.83; 95% CI, 0.71–0.97; p = 0.05) in patients receiving letrozole.[29,30] This suggests that the risk reduction in distant recurrence at 25.8 months may have a positive effect on overall survival at 76 months.

Comparative Efficacy

To date, there have been no published data from prospective randomized trials comparing AIs. However, the similarity in inclusion and exclusion criteria and follow-up duration in the ATAC and BIG 1–98 trials allowed a preliminary retrospective, though indirect, comparison of the effects of letrozole and anastrozole versus tamoxifen, using the number-needed-to-treat approach.[31] Using data from the 68-month analysis of the ATAC trial and the 76-month censored analysis of the BIG 1–98 trial, it was demonstrated that the number needed to treat to prevent an early distant recurrence was 100 for letrozole and 303 for anastrozole. The number needed to treat to prevent one death was 63 for letrozole and 161 for anastrozole. These results underscore the need for head-to-head prospective studies, such as the ongoing Femara versus Anastrozole Clinical Evaluation (FACE) trial, that may better characterize clinical differences between AIs.[32]


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