Switch from Adjuvant Tamoxifen to Exemestane Improves Outcomes in Postmenopausal Pts With Early Breast Cancer

ATLANTA—Postmenopausal women who are receiving tamoxifen as adjuvant therapy for early-stage breast cancer have a reduced risk of relapse and death if they switch to the aromatase inhibitor exemestane (Aromasin) after several years, researchers reported at the 2006 ASCO Annual Meeting (late-breaking abstract 527). Judith M. Bliss, MSc, director of the Institute of Cancer Research's Clinical Trials & Statistics Unit, Sutton, UK, presented the updated results of the trial—the Intergroup Exemestane Study (IES)—including the first mature survival data.

In the trial, women who had undergone resection of early breast cancer and who remained disease-free after 2 to 3 years of tamoxifen therapy were randomized to continue tamoxifen or to switch to exemestane for an additional 2 to 3 years, for a total of 5 years of hormonal therapy, with continued follow-up thereafter. Initial results of the trial have been previously reported (N Engl J Med 350:1081-1092, 2004).

At the time of the updated analysis, the median duration of follow-up since randomization was 56 months, Prof. Bliss said. Intention-to-treat (ITT) analyses were based on 2,372 women who continued taking tamoxifen and 2,352 women who switched to exemestane. In addition, some analyses were based only on patients who had estrogen-receptor (ER)-positive or ER-unknown disease, excluding the 3% of patients found to have ER-negative disease "who could not have been expected to benefit from either treatment," Prof. Bliss said.

The actuarial rate of disease-free survival was about 84% in the exemestane group and 80% in the tamoxifen group in the ITT population, corresponding to a significant, nearly one-fourth reduction in the risk of events (breast cancer recurrence, contralateral breast cancer, or intercurrent death) in favor of exemestane (HR 0.76).

A risk reduction favoring exemestane was also present and significant in an analysis restricted to the women known to have ER-positive/ER-unknown breast cancer (84% vs 81%; HR 0.75) and remained so after adjustment for nodal status, receipt of chemotherapy, and use of hormone replacement therapy (HR 0.74).

Turning to the cumulative hazard rate for disease-free survival in the latter population, Ms. Bliss noted, "The divergence of the curves seen early on is really persisting throughout our follow-up period observed to date." Relapses continue to occur during this period, she commented, "as is maybe typical of ER-positive disease." Subgroup analyses showed that the benefit in this population was mirrored in subgroups created according to nodal status, receipt of chemotherapy, duration of tamoxifen before randomization, and patient age.

The actuarial rate of overall survival tended to be higher with exemestane than with tamoxifen in the ITT population (90% vs 89%; HR 0.85; P = .08). The finding was again similar in the ER-positive/ER-unknown population (90% vs 89%; HR 0.83; P = .05) and remained so after adjustment for nodal status, receipt of chemotherapy, and use of hormone replacement therapy (HR 0.83; P = .04). Subgroup analyses again showed that subgroups of women benefited similarly to the group overall.

Additional, unadjusted analyses also significantly favored switching to exemestane over continuing tamoxifen in terms of breast-cancer-free survival (hazard ratios in the ITT population and in the ER-positive/ER-unknown population, 0.76 and 0.75, respectively); time to distant recurrence (0.83 and 0.82); and time to contralateral breast cancer (0.57 and 0.56). "With 2 to 3 years' post-treatment follow-up, early disease-related benefits previously reported appear to be maintained," Prof. Bliss said.

Safety Analysis

The incidence of thromboembolism was significantly higher with tamoxifen than with exemestane (3.1% vs 1.9%), although this tended to be driven by events while on treatment, Prof. Bliss said. "There is no overall difference in the rate of myocardial infarction [MI]," she continued. "If anything, any risk or effects of MIs appear restricted to patients with a history of hypertension, just really reinforcing the need for those patients to be properly monitored in routine practice."

The exemestane-treated patients had significantly higher incidences of fracture (7.0% vs 4.9%) [see also article on page 50 on effects of vitamin D on exemestane-related bone loss], and the tamoxifen-treated patients had significantly higher rates of serious gynecologic events (9.8% vs 6.4%). "We can conclude that exemestane is safe and well tolerated," Prof. Bliss said. "The switching strategy appears to minimize the adverse risks of both agents."