Concerns crop up about aromatase inhibitors. (Musculoskeletal Problems, Fractures).

SAN ANTONIO -- Updated results of the world's largest breast cancer treatment trial have injected a cautionary note into efforts to develop the aromatase inhibitors as breast cancer chemoprevention agents.

Extended follow-up data from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial were presented at a breast cancer symposium sponsored by the San Antonio Cancer Institute. While the data were largely quite favorable to the aromatase inhibitor anastrozole (Arimidex), they nevertheless provided mixed results with regard to safety.

The use of anastrozole for adjuvant therapy in women with breast cancer in ATAC carried markedly lower risks of gynecologic and thromboembolic complications than did adjuvant tamoxifen. Still, this advantage was partially offset by significantly higher rates of musculoskeletal disorders, joint symptoms, and fractures. (See table.)

This finding is particularly relevant because multiple large, long-term, multicenter phase III clinical trials of aromatase inhibitors for breast cancer chemoprevention are getting underway this year. Among them are the International Breast Intervention Study-2, which will randomize up to 12,000 postmenopausal women at high risk for breast cancer and 4,000 women with ductal carcinoma in situ to 5 years of anastrazole, tamoxifen, or placebo.

Some listeners shrugged off the new ATAC data showing increased musculoskeletal and bone complications in anastrozole-treated patients, reasoning that concomitant bisphosphonate therapy should minimize these problems. Others were more concerned.

"It's somewhat discomfiting that in large phase III trials we're using these drugs that we're pretty sure are going to have some sort of iatrogenic effect on bone.... Bone is clearly a major concern with aromatase inhibitors-and there may be others as yet unknown, like cognition," Mitchell Dowsett, Ph.D., said in commenting on the new findings presented by ATAC principal investigator Dr. Aman Buzdar.

And the ATAC findings were no fluke, said Dr. Dowsett, an endocrine biochemist at the Royal Marsden Hospital, London.