ATAC Data Ease Concerns About Risk of Bone Fractures

COPENHAGEN, Denmark—The risk and incidence of bone fractures associated with the use of the aromatase inhibitor anastrozole (Arimidex) for treatment of early breast cancer in postmenopausal women appears to stabilize after peaking at 2 years, easing some of the major concerns about the drug.

Anthony Howell, MD, chairman of the ATAC (Arimidex, Tamoxifen Alone or in Combination) steering committee and professor of oncology, University of Manchester, UK, presented the data at the European Cancer Conference (ECCO 12) (abstract 676).

ATAC, the world’s largest ongoing multicenter, double-blind study of breast cancer treatment, compares the efficacy and safety of anastrozole 1 mg once daily with tamoxifen (Nolvadex) 20 mg once daily, as adjuvant therapy for postmenopausal women with hormone-receptor-positive early breast cancer. The trial included woman who were eligible for, but had not received, prior adjuvant hormonal therapy. Patients were randomized to receive anastrozole (n = 3,125), tamoxifen (n = 3,116), or anastrozole and tamoxifen combined (n = 3,125).

Previous reports from ATAC showed that over a median follow-up of 33 months, anastrozole increased disease-free survival by 19% and reduced recurrence by an absolute difference of 1.8%, compared with tamoxifen. The incidence of new tumors in the opposite breast was also reduced by more than 58%. Data updated when the median follow-up reached 47 months showed that the gap in absolute difference in recurrence had widened to 2.6% in favor of anastrozole

"The reduction in disease occurrence and the favorable safety profile, especially the thromboembolic events and the absence of a tumor agonist effect sometimes seen with tamoxifen, are reason why the overall risk benefit for anastrozole for women with early breast cancer remains positive," Dr. Howell said.

Nonetheless, physicians need to be cautious in their use of anastrozole. "We should still wait for the overall survival data next year," Dr. Howell said.

Bone Fracture Data

This tempered enthusiasm is caused by the fact that anastrozole has been associated with an increased risk of bone fractures. Because of the increased estrogen deprivation with anastrozole, it is not unexpected that women on this drug might have a higher risk of fractures than those on tamoxifen, a drug known to have a mildly positive effect on bone mineral density.

Although the ATAC study confirmed that there are slightly more fractures in women treated with anastrozole (range 0.93 to 1,57), than with tamoxifen (range 0.58 to 1.37), the difference is not statistically significant, Dr. Howell said, and the overall benefit-to-risk in early breast cancer remains unchanged, favoring anastrozole.

In this newest analysis, the ATAC researchers looked at data on fracture incidence at 6-month intervals for up to 48 months of treatment.

Said Dr. Howell, "We found that at the first analysis, after 31 months median duration of treatment, the incidence of fractures was 5.9% in anastrozole patients, compared with 3.7% in tamoxifen patients—nearly 60% greater. But, when the data were updated at 37 months, the incidence was 7.1% vs 4.4%, so still around a 60% difference. The risk had not worsened."

In fact, he said, the 6 monthly fracture rates for anastrozole reached a plateau after 24 months, with the maximum difference between the two treatments being seen at 18 and 24 months. "By the last follow-up at 48 months, the increase in risk was down to about one third higher for anastrozole," he said. There were similar patterns for fractures of the hip, spine, and wrist.