To the Editor:

Coombes et al¹ reported results of a 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 loss and related effects were also seen with anastrozole and letrozole. In the ATAC trial, anastrozole treatment was associated with a progressive decline in bone mineral density, while there was a slight increase with tamoxifen.5 Bone fractures were also significantly more frequent with anastrozole than with tamoxifen (7.1% v 4.4%, respectively; P < .001), at a median therapy duration of 37 months.6 In MA.17, there were more new cases of osteoporosis in patients receiving letrozole than in those on placebo (5.8% v 4.5%, respectively; P = .07), but similar incidences of fractures between patient groups (3.6% for letrozole and 2.9% for placebo; P = .24).3 Ongoing IES, ATAC, and MA.17 bone substudies will provide more insight into the longer-term effects of aromatase inhibitors on bone loss. An ongoing international trial program, the Zometa-Femara Adjuvant Synergy Trials (ZO-FAST/Z-FAST), is evaluating the benefits of adding an intravenous bisphosphonate, zoledronic acid, to adjuvant letrozole therapy, either upfront or delayed until a major decrease in bone mineral density or a fracture occurs.

The IES trial also reported exemestane-associated toxicities that have not been described for the nonsteroidal aromatase inhibitors—a significantly higher incidence of visual disturbances and diarrhea as well as cardiovascular disease and deaths from vascular causes.1 Whether these side effects are related to the steroidal nature of exemestane, or to its androgenic or estrogenic metabolites, remains to be clarified. We would also be interested to know whether androgenic side effects or pronounced weight gain, previously described in shorter-term exemestane studies,7 occurred within the IES protocol, as such toxicities would be of high clinical relevance in a collective of potentially healthy women who will take the agent for a long time.

In summary, there may in fact be safety differences between exemestane and the nonsteroidal aromatase inhibitors that do not favor exemestane. It will be important to further, and comprehensively, assess the long-term effects of all three aromatase inhibitors on bone loss and other safety issues during adjuvant therapy.

Author's Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Henning T. Mouridsen, Novartis. Honoraria: Henning T. Mouridsen, Novartis. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Authors Disclosure Declaration form and the ‘Disclosures of Potential Conflicts of Interest’ section of Information for Contributors found in the front of every issue.