Exemestane following tamoxifen in postmenopausal women with primary breast cancer.

Abstract

large and well-designed randomized trial of sequential adjuvant endocrine therapy for estrogen receptor–positive primary breast cancer in postmenopausal women (Intergroup Exemestane Study [IES]). Following 2 to 3 years of tamoxifen therapy, patients were randomly assigned to receive the steroidal aromatase inhibitor, exemestane, or to continue on tamoxifen for the remainder of 5 years’ total treatment. Compared with standard tamoxifen for 5 years, switching to exemestane midcourse significantly improved disease-free survival (DFS) at a median follow-up of 30.6 months, which was characterized by a 32% reduction in risk of recurrence, new contralateral breast cancer, or death, which corresponded to an absolute DFS benefit of 4.7% at 3 years after random assignment. These IES results are consistent with improvements seen in previously reported large randomized adjuvant trials that evaluated the nonsteroidal aromatase inhibitors anastrozole and letrozole. In the Arimidex, Tamoxifen Alone, or in Combination (ATAC) trial, 5 years of anastrozole resulted in an absolute improvement in estimated 4-year DFS of 2.4% compared with 5 years of tamoxifen, at 47 months’ median follow-up. 2 The MA.17 trial followed 5 years of tamoxifen with randomization to 5 years of letrozole or placebo, and at 2.4 years’ median follow-up, there was a 6% absolute improvement in estimated 4-year DFS in the letrozole arm compared with the placebo arm. 3 The optimal use of these aromatase inhibitors as adjuvant therapy, either instead of, or sequenced with, tamoxifen, remains to be determined, and ongoing trials such as the Breast International Group study BIG 1-98, which is addressing these issues with letrozole, should provide more definitive direction. I am concerned with the safety profile reported for exemestane in the IES trial. It was particularly disappointing that exemestane was associated with substantial bone loss and related consequences, given preclinical study results suggesting a bone-protecting effect. 4 Exemestane treatment resulted in higher incidences of osteoporosis (7.4% v 5.7%, respectively; P .05) and fractures (3.1% v 2.3%, respectively; P .08) than tamoxifen. 1 Some bone