Fracture Risk With Anastrozole Levels off at Three Years in Postmenopausal Women

Neil Osterweil

September 23, 2003

Sept. 23, 2003 (Copenhagen) — The risk of bone fracture associated with the use of anastrozole for treatment of early breast cancer in postmenopausal women appears to reach a plateau and does not worsen after about three to four years, reported researchers from the large-scale ATAC (Arimidex, Tamoxifen Alone or in Combination) trial.

The finding should allay some concerns about the use of anastrozole for treatment of early breast cancer in older women, according to Anthony Howell, MD, professor of oncology at the University of Manchester and a medical oncologist at the Christie Hospital in Manchester, U.K.

"There's no doubt that there are more fractures with anastrozole," said Dr. Howell at a media briefing held here during the 12th annual European Cancer Conference. "But there's no difference between anastrozole and tamoxifen for hip fractures, and the six-month fracture rate remains relatively stable in both groups, with anastrozole stabilizing after 36 months, and the bone-sparing properties of tamoxifen should be taken into account when you interpret these results. In view of the reduction in disease recurrence and the favorable safety profile with other things as far as anastrozole is concerned — especially in endometrial cancer and thromboembolic events are concerned — our view is that the overall risk benefit ratio for anastrozole for women with early breast cancer remains positive."

Previously released data from the trial, involving more than 9,000 women in 21 countries, showed that over a median follow-up of 33 months, disease-free survival was 19% better, and the incidence of new tumors in the contralateral breast was 58% less with anastrazole than with tamoxifen. An update of the data at a median of 47 months showed an absolute difference in favor of anastrozole.

For the current analysis, the researchers looked at data on fracture incidence at six-month intervals for up to 48 months of treatment. Fracture incidence from the ATAC study was assessed every six months up to 48 months of treatment. The analysis included differences in patterns of time-to-fracture for anastrozole vs. tamoxifen.

In the first analysis of results from 31 months of therapy, the fracture incidence was 5.9% in women taking anastrozole and 3.7% for those receiving tamoxifen, a risk ratio of about 1.6. When an update of safety data was performed at 37 months, the risk of fractures, and the difference between the two drugs, was about the same, Dr. Howell said.

In addition, the risk of hip fracture, one of the most important concerns in this group of patients, was not statistically different between the two groups. The risk of spine and wrist/colles fractures were also statistically similar, according to Dr. Howell.

But is the increased risk of fracture with anastrozole great enough to mitigate against its use given its apparently superior efficacy and favorable safety profile in other parameters?

"The short-term data show the number of recurrences [with anastrozole] is clearly lower; the absolute difference at this point is about 2.5%," said Debu Tripathy, MD, professor of medicine and director of the breast cancer research center at the University of Texas Southwestern Medical Center, in Dallas, who commented on the study in an interview with Medscape. "Of course, the fracture difference is also about 2%, but the consequences of a fracture and the consequences of a recurrence are very different."

Dr. Tripathy concluded, "I think in the end which one wins out long term is going to be difficult to say; I don't think you should underestimate the problem with osteoporosis, though, because that is really a long-term issue."

Dr. Tripathy noted that the women in the ATAC trial were less at risk to die from breast cancer than from other causes, and they could be subject to late complications of osteoporosis. "So this is a very tricky issue trying to counsel women now when we don't have data 20 years down the line what are your bones going to look like when you're 70, 80 years old."

"You have to look carefully, but you have to look at the total picture," said Harry Bartelink, MD, chairman of radiotherapy at the Netherlands Cancer Institute in Amsterdam, in an interview with Medscape. "The risk of fractures is, of course, that it happens to older women, and they have to be operated on and you have complications from the surgery, so that's something you have to take seriously."

On the other hand, said Dr. Bartelink, who is familiar with the study data, the advent of relatively simple genetic testing with microarrays can help to differentiate between patients who might benefit most from anastrozole (such as women with tumors that are positive for HER2) and those who may benefit from tamoxifen. "In four or five years we will be able to select which is the best treatment and then the bone fractures are not a problem anymore, because then the gain in survival and disease response is much larger," Dr. Bartelink told Medscape.

ECCO 12: Abstract 676. Presented Sept. 24, 2003.

Reviewed by Gary D. Vogin, MD

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