New evidence about the breast cancer drug anastrozole (Arimidex) shows that the incidence of a major side-effect - bone fractures - appears to stabilize after reaching a peak at two years of treatment, easing some of the concerns about the drug.

This finding is the latest to come from evidence provided by the world's largest international study of breast cancer treatment, the ATAC trial [Arimidex, Tamoxifen Alone or in Combination], which compared the aromatase inhibitor anastrozole with breast cancer's current gold standard hormone treatment tamoxifen, and with both treatments combined.

The trial, involving more than 9,000 postmenopausal women in 21 countries, revealed last year that after a median follow-up of patients of 33 months, anastrozole enhanced disease-free survival by 19% and cut the incidence of new tumors in the opposite breast by 58% compared to tamoxifen. This represented an absolute difference of 1.8% in favor of anastrozole. An update at 47 months median follow up showed that the gap had widened to an absolute difference of 2.6% in favor of the newer drug. Overall survival comparisons from the trial should be available next year.

Professor Anthony Howell, chairman of the ATAC steering committee, told a news briefing at ECCO 12 - the European Cancer Conference, that while it was clear that further results were adding to the evidence that anastrozole may in the future supplant tamoxifen, doctors needed to be cautious. "We should still wait for that overall survival data next year," he said.

A concern about anastrozole has been the risk of bone fractures. Depriving the body of estrogen reduces the risk of breast cancer recurring because many breast cancers 'feed' off this hormone. But, one consequence of estrogen deprivation is that bones become vulnerable. Aromatase inhibitors such as anastrozole produce profound estrogen deprivation, so it would not be unexpected that women on anastrozole might be more at risk of fractures than those on tamoxifen, a drug that is known to have a mildly positive effect on bone density.

Therefore, bone fracture was a pre-defined adverse event in ATAC's main protocol; one of the important questions posed in the trial was - if anastrozole turned out to be better than tamoxifen at preventing recurrence of breast cancer or of primary tumors in the other breast, would this benefit outweigh the downside of any added incidence of fractures?

Patients' fracture rates were assessed every six months as a proportion of patients with a first fracture, and these analyses were repeated for fractures of the hip, spine and wrist.

Howell, a medical oncologist at the Christie Hospital, Manchester, UK said: "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 was updated at 37 months the incidence was 7.1% versus 4.4%, so still around a 60% difference. The risk had not worsened. In fact, the six-month 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 a third higher for anastrozole. There were similar patterns for fractures of the hip, spine and wrist."

Howell added: "Anastrozole does lead to an increased bone fracture incidence compared to tamoxifen. But, the positive news is that the fracture rate does appear to peak and then stabilise. So, the overall benefit for patients with early breast cancer remains with anastrozole. We have no idea why the fracture rate stabilizes, but clearly this is important for patients. It is possible that it will climb again but since the curves have been parallel for some time this seems unlikely.

"It is now important to see what happens when patients stop their treatment after five years and we plan to do bone density measurements at the end of the trial."

The trial shows that the combination of tamoxifen and anastrazole is equivalent to tamoxifen (possibly because anastrozole lowered estrogen dramatically and there was some evidence that tamoxifen acted as an estrogen agonist in a low estrogen environment).

It was potentially detrimental, Howell said, for patients to switch from tamoxifen to anastrozole, so the advice was that patients should continue with whichever drug they were on.

He concluded: "It is important that tamoxifen does not suffer from the comparison in this trial because it is still a very good treatment. In developing countries with limited resources to pay for more expensive new drugs, it is particularly appropriate to continue to use tamoxifen." SOURCE:
ECCO 12 - the European Cancer Conference, September 24, 2003, Copenhagen, Denmark