SAN ANTONIO — The landmark Study of Tamoxifen and Raloxifene had an intriguing paradoxical outcome: Although the two drugs proved equally effective in preventing invasive breast cancer, tamoxifen turned out to be far better at preventing noninvasive breast cancers, Dr. Victor G. Vogel said at a breast cancer symposium sponsored by the Cancer Therapy and Research Center.
“This was somewhat surprising,” he admitted. “I really don't have a biologic or molecular explanation for these data at this time.”
STAR involved 19,747 postmenopausal women at high risk for breast cancer who were randomized to daily tamoxifen or raloxifene and followed for an average of 4 years. Invasive breast cancer—the primary study end point—occurred in 163 women on tamoxifen and 168 on raloxifene, compared with a predicted 312 cases per study arm, based on use of the Gail breast cancer risk model in lieu of a placebo arm.
This worked out to a cumulative incidence of 25.1 cases of invasive breast cancer per 1,000 patients at 6 years with tamoxifen and an almost identical 24.8/1,000 with raloxifene, noted Dr. Vogel of the University of Pittsburgh and the National Surgical Adjuvant Breast and Bowel Project.
In contrast, the 80 cases of in situ breast cancer—either ductal carcinoma in situ, lobular carcinoma in situ, or mixed lesions—in the raloxifene arm constituted a rate 40% higher than with tamoxifen, although the difference in this secondary end point was of only borderline statistical significance. The finding was unexpected in light of the fact that in situ breast cancer is a well-established powerful risk factor for development of invasive breast cancer.
A gratifying and clinically important related finding in STAR was that tamoxifen and raloxifene proved of equal benefit in preventing invasive breast cancer in women with a history of precancerous breast lesions at study entry, he added.
Dr. Leslie G. Ford commented that despite the apparently higher rate of noninvasive breast cancer with raloxifene compared with tamoxifen in STAR, the overall advantage goes to raloxifene because of its lower rates of thromboembolic events, endometrial cancer, and cataracts.
“We consider raloxifene the winner of STAR,” declared Dr. Ford, associate director of clinical research in the division of cancer prevention at the National Cancer Institute, the trial's primary sponsor.
She noted that while the 38% reduction in the relative risk of uterine cancer in the raloxifene arm didn't quite reach statistical significance, more than twice as many women in the tamoxifen arm underwent hysterectomy for noncancer indications. And a finding of endometrial hyperplasia at hysterectomy was six times more frequent in tamoxifen users.
“There's no question that if these hyperplasias had gone on without the uterus being removed, we would have had a highly significant result in terms of uterine cancer,” Dr. Ford observed.
The cumulative 6-year incidence of thromboembolic events was 21 cases/1,000 treated women in the tamoxifen arm and 16/1,000 with raloxifene, for a highly significant 30% relative risk reduction.
“This was another surprise to us. Although both tamoxifen and raloxifene carry in their labels an increased risk for thromboembolic events, in fact raloxifene was better than tamoxifen,” she said.
The raloxifene group also had a 21% reduction in the relative risk of developing cataracts.
The in situ breast cancer rate in the raloxifene arm was 40% higher than with tamoxifen. DR. VOGEL