SAN ANTONIO – The aromatase inhibitor anastrozole has emerged as a major new agent for the primary prevention of breast cancer in high-risk postmenopausal women on the strength of a 53% reduction relative to placebo in the IBIS-II trial.
"Our results provide substantial support for the use of anastrozole as the treatment of first choice for prevention of breast cancer in high-risk postmenopausal women," Jack Cuzick, Ph.D., declared in presenting the study results at the San Antonio Breast Cancer Symposium.
Dr. Jack Cuzick
IBIS-II (the International Breast Cancer Intervention Study II) was an 16-country, double-blind, randomized, placebo-controlled trial in which 3,864 postmenopausal women aged 40-70 years at high risk for breast cancer were randomized to 1 mg of oral anastrozole (Arimidex) or placebo daily for 5 years.
At 7 years of follow-up, the cumulative incidence of all breast cancers in an intent-to-treat analysis was 5.6% with placebo and 2.8% in the anastrozole group, for a highly significant 53% reduction in risk. This translates into a number needed to treat of 36; that is, it’s estimated that treating 36 women for 5 years will prevent one breast cancer in 7 years.
The incidence of estrogen receptor–positive invasive breast cancer was 3.3% in controls, compared with 1.4% with anastrozole, for a 58% relative risk reduction, added Dr. Cuzick, head of the Cancer Research U.K. Center for Cancer Prevention and director of the Wolfson Institute of Preventive Medicine at Queen Mary University of London.
The incidence of high-grade tumors was 35% lower in the anastrozole group. With additional years of follow-up, this will probably translate into a reduction in deaths from breast cancer in the anastrozole group. The plan is for at least 10 years of follow-up in IBIS-II.
Among women on placebo, 72% completed 5 years, as did 68% assigned to anastrozole.
"One of the most important findings of this trial is that the drug was very well tolerated, with only an absolute 4% difference in compliance. So drug side effects didn’t influence compliance in any major way," Dr. Cuzick observed.
The incidence of other cancers was 3.6% with placebo and 2.1% with anastrozole, for a significant 42% relative risk reduction. This was mostly driven by markedly fewer cases of skin cancer and colorectal cancer in patients on the aromatase inhibitor.
"We don’t really understand this. It’s another exciting possibility – that this drug may have an effect in reducing the risk of other cancers – which we will continue to explore," he continued.
Going into the trial, the anastrozole side effect of chief concern was fractures, but under the study protocol all participants had a baseline bone mineral density scan and were placed on a bisphosphonate if indicated. That’s presumably the explanation for the finding that the incidence of fractures didn’t differ significantly between the two study arms.
Musculoskeletal pain was reported by 64% of anastrozole-treated patients and 58% on placebo. The incidence of moderate musculoskeletal pain was 22% with anastrozole and 19% with placebo, while severe pain was reported by 8% of women in the anastrozole group, compared with 6% on placebo.
Pointing to the 58% incidence of musculoskeletal side effects in the placebo group, Dr. Cuzick said that "there’s a general perception that the aromatase inhibitors are very toxic and cause a lot of aches and pains. But 90% of the aches and pains in this study had nothing to do with the drug. They’re just a reflection of the fact that in the postmenopausal years women do get aches and pains."
Vasomotor symptoms occurred in 49% of the placebo group and 57% of women on anastrozole, a statistically significant difference.
Dr. Cuzick said that he believes the sharp reduction in breast cancer seen with anastrozole in IBIS-II is probably a class effect common to the other aromatase inhibitors. In the MAP.3 trial, an earlier study with shorter follow-up (N. Engl. J. Med. 2011;364:2381-91), exemestane showed results similar to those seen in IBIS-II. He added that the greater size and duration of IBIS-II, coupled with the fact that contralateral breast cancer rates continue to be lower at 10 years of follow-up in the anastrozole breast cancer treatment trials, makes him "quite confident" in declaring anastrozole to be the drug of first choice for prevention.
Audience member Dr. Pamela J. Goodwin rose to take issue with that assertion. She noted that there are two approved agents for this indication – tamoxifen and raloxifene – yet placebo was used as the comparator in IBIS-II.
"The evidence is indirect evidence," Dr. Cuzick replied. "Anastrozole and exemestane have shown very, very similar results. The aromatase inhibitors show larger risk reductions than tamoxifen or raloxifene, and overall serious side effects are substantially less. For that reason we think they are the appropriate first choice."