Benefit With Aromatase Inhibitors in the Adjuvant Setting for Postmenopausal Women With Breast Cancer

Henning T. Mouridsen, MD, PhD; Nicholas J. Robert, MD

In This Article

Early Adjuvant Trials

ATAC -- Arimidex, Tamoxifen Alone or in Combination

Study Design. This large randomized phase 3 study was designed to compare anastrozole with tamoxifen as early adjuvant therapy and also to evaluate the combination of anastrozole plus tamoxifen, with all treatments for 5 years (Figure 1).[25,26,27] Postmenopausal women with operable early breast cancer (N = 9366) were randomized after surgery to receive anastrozole alone (1 mg/d), tamoxifen alone (20 mg/d), or the combination of both agents, for 5 years. The primary end point was DFS (defined as time from randomization to local or distant recurrence, new primary breast cancer, or death from any cause), and secondary end points included incidence of contralateral breast primary cancers, time to recurrence (not including patients who had died from non-breast cancer causes before recurrence), time to distant recurrence, and survival.[25]

Results. Patient characteristics were well balanced between the 3 groups ( Table 2 ). Analyses were performed at median follow-up times of 33, 47, and 68 months.[25,26,27] Results showed no difference in any end point between the tamoxifen-only group and the combination tamoxifen-anastrozole group. It is possible that marked estrogen suppression caused tumor cells to become hypersensitive to the estrogenic effects of tamoxifen; however, the reasons for the similarity of responses in the 2 groups are not fully understood.

In comparisons of the anastrozole-alone and tamoxifen-alone groups, the 68-month follow-up analysis showed that in the overall intent-to-treat population, hazard ratios for DFS and time to recurrence significantly favored anastrozole over tamoxifen and the combination arm ( Table 3 ).[27] There was a 13% relative risk reduction in probability of recurrence with anastrozole versus tamoxifen. In terms of time to recurrence, the hazard ratio (HR) was 0.79 and the absolute difference of 1.7% at 3 years increased to 3.7% at 6 years in the hormone receptor-positive subpopulation.[27] The reduction in overall rate of contralateral breast cancer with anastrozole versus tamoxifen was significant at the 33-month follow-up visit (HR 0.42; P = .007) and the 68-month follow-up visit (HR 0.58, P = .01); however, the reduction was only borderline (HR 0.62; P = .06) at the 47-month follow-up visit. The overall reduction in incidence of contralateral invasive breast cancer with anastrozole treatment was significant at 33 and 47 months of follow-up (HR 0.30, P = .001; and HR 0.57, P = .044).[25,26] Survival was similar with the 2 treatments.

Analysis of time to recurrence in the ATAC trial indicated that receptor status was a predictor of efficacy. Patients with ER+/progesterone receptor-negative (PgR-) tumors derived much greater benefit, in time to recurrence, from anastrozole compared with tamoxifen than did patients with ER+/PgR+ tumors ( Table 4 ), but the mechanism for that difference in activity will require further study.[28] Neither nodal status, tumor size or grade, nor prior adjuvant chemotherapy affected these results.

In subgroup analyses in the ATAC trial at the 47-month follow-up visit, 2 subgroups of patients, those with 4 or more affected nodes and those who received prior chemotherapy, were reported to have failed to benefit from anastrozole vs tamoxifen (HR 0.98, confidence limit [CL] = 0.76-1.28; and HR 0.95, CL = 0.72-1.25, respectively).[26]

The safety profile of anastrozole was consistent in all follow-up analyses.[25,26,27] The benefits of estrogen suppression were seen in the anastrozole group, which had significantly fewer endometrial cancers, occurrences of vaginal bleeding, cerebrovascular events, and venous thromboembolic events. The tamoxifen group had significantly fewer musculoskeletal disorders and fractures ( Table 5 ). A progressive loss of bone mineral density was observed in the anastrozole group compared with the tamoxifen group.[29]

A large (n = 1021) quality of life (QOL) study of ATAC trial patients, using the Functional Assessment of Cancer Therapy - Breast (FACT-B) scale and an endocrine subscale at 0 to 24 months during the study concluded that tamoxifen and anastrozole were associated with similar overall QOL impact, showing gradual improvement over time. Some endocrine-related symptoms worsened initially and recovered partially over the 2 years.[30]

BIG 1-98 -- Breast International Group Trial (Monotherapy Arms)

Study Design. The BIG 1-98 trial is a randomized, double-blind, double-dummy, multicenter, controlled phase 3 trial. Initially it was designed to compare letrozole (2.5 mg/d) with tamoxifen (20 mg/d) as early adjuvant therapy, but it was later amended to include also 2 early sequential therapy strategies (letrozole before or after tamoxifen).[24,31] The trial is being conducted by the BIG/International Breast Cancer Study Group and is also known as the BIG FEMTA trial. Patients are postmenopausal women with ER+ and/or PgR+ tumors who were randomized after complete tumor excision. Adjuvant radiotherapy and chemotherapy were allowed during the trial, and patients were stratified by adjuvant chemotherapy, type of surgery, and participating study center. In this section, we consider only the monotherapy arms.

The primary end point of BIG 1-98 is DFS defined as time from randomization to locoregional or distant recurrence, invasive contralateral breast cancer, second (non-breast) malignancy, or death without recurrence. Secondary end points include locoregional and distant DFS, OS, and safety. Evaluations of bone metabolism and lipid metabolism are planned in substudies.[31] Patient accrual was completed in April 2003. The core analyses of tamoxifen vs letrozole (Figure 2) included patients in the tamoxifen monotherapy arm and patients in the tamoxifen followed by letrozole arm (censored at 2 years) vs patients in the letrozole in the monotherapy arm and patients in the letrozole followed by tamoxifen arm (censored at 2 years), a total of 4007 vs 4003 patients.[32]

Figure 1.

ATAC trial schema.

Results. Patient characteristics were well balanced between the 2 groups ( Table 6 ). With a median follow-up of 25.8 months the HR for DFS significantly favored letrozole over tamoxifen with a 19% (95% CI, 7% to 30%, P = .003) risk reduction in probability of an event, and a 27% risk reduction in time to distant recurrence.[32] In the letrozole-treated patients, a 14% reduction of mortality (P = .16) was observed.[32] Further presentation of data from this study will await peer-reviewed publication of final results.

TEAM -- Tamoxifen Exemestane Adjuvant Multinational Trial

Study Design. The TEAM trial is an open-label, multinational, phase 3 trial being conducted in approximately 4400 postmenopausal women with ER+ and/or PgR+ early breast cancer.[24,33] It was begun in 2001 by the Cancer Research Campaign Trials Unit in the United Kingdom. Patients are randomized to receive exemestane (25 mg/d) or tamoxifen (20 mg/d) as adjuvant monotherapy for 5 years, then stratified according to hormone receptor status, prior chemotherapy, and nodal status. The primary end point is DFS, and secondary end points include OS, incidence of new primary breast cancers, and safety parameters.[33] In addition, 5 substudies will be used to separately analyze endometrial changes, lipid profiles, QOL, tolerability of therapy, and bone changes. A meta-analysis of overall drug efficacy will use data from these combined substudies.[24]

Because of recent results of the ICCG 96 trial (see description below) showing that switching from tamoxifen to exemestane after 2 to 3 years improves DFS compared with remaining on tamoxifen, the TEAM trial has been amended to effect such a switch.

Preliminary results. Initial data from a small lipid substudy showed that exemestane and tamoxifen both stabilized total cholesterol and high-density lipoprotein cholesterol levels. Exemestane, but not tamoxifen, slightly increased low-density lipoprotein cholesterol and significantly increased triglycerides.[34] These changes were similar to those associated with anastrozole in postmenopausal women.[35]

The MA.27 Trial

Study Design. This randomized phase 3 trial is designed to compare anastrozole with exemestane for adjuvant therapy and, in addition, to analyze the role of adding celecoxib.[36] The trial is coordinated by the National Cancer Institute of Canada Clinical Trials Group with the participation of centers in Canada and the United States. Following surgery, postmenopausal patients with receptor-positive breast cancer are stratified according to nodal status and prior adjuvant chemotherapy, and randomized to receive exemestane (25 mg/d) or anastrozole (1 mg/d) for 5 years. In addition, each of these two groups are randomly assigned to receive either celecoxib (400 mg twice daily) or placebo (twice daily), continued for 3 years. The primary end point is DFS, and secondary end points include OS, time to distant recurrence, evidence of contralateral breast cancer, and long-term clinical and laboratory safety. The MA.27 trial is planned to enroll 6830 patients, and started in 2004. Due to reports of cardiotoxicity, randomization to the celecoxib arms has now been closed.


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