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139th National Cancer Advisory Board

Dr. Wickerham briefly reviewed the structure and results of the NSABP B14 trial of tamoxifen, which he described as the most commonly prescribed breast cancer drug in the world. The design was among the first node-negative/receptor-positive trials in the world. It began in 1981 and arguably is a landmark study in oncology, not just breast cancer oncology. With 2,800 who were randomized to placebo or tamoxifen, NSABP was able to demonstrate that tamoxifen improved both disease-free survival and survival in general and that those benefits now have gone through 15 years of followup. In addition, it was found that women taking tamoxifen had a 50 percent reduction in new primaries in the opposite breast. This had been seen also in other trials around the world and in the PETO overview of all the tamoxifen studies, and led to the design of the first NSABP breast cancer prevention trial (BCPT-P1).

BCPT-P1 enrolled otherwise healthy individuals at an increased risk for the future development of breast cancer and assigned them to either tamoxifen or placebo for a 5-year period in a double-blinded trial. Gail Model variables were used to quantify their breast cancer risk. The minimum score to be eligible for BCPT-P1 was a 1.66 percent risk of developing breast cancer in the next 5 years. BCPT-P1 began in 1992 with more than 13,000 women entered in the study. Premenopausal (35 years of age and older) women were included in the trial, 39 percent were under the age of 50, and family history accounted for most of the risk. Three-quarters of them had one more first-degree relative, which translated into an average Gail risk of a little more than 3 percent. Seventeen percent had a risk of 5 percent or greater. Only 6 percent had a prior history of lobular carcinoma in situ (LCIS), and 9 percent had atypical hyperplasia. BCPT-P1 results were announced in 1998 and were able to show that tamoxifen was highly effective in reducing the risk of invasive breast cancer (mediating a 49 percent reduction in invasive disease). The benefits were demonstrable in all of the subgroups, but the groups that appeared to benefit the most were those who came into the trial with a prior history of LCIS or atypical hyperplasia. The LCIS group has a risk of about 13 cases per 1,000 per year and the tamoxifen dramatically reduced that. The atypical hyperplasia reduction by 86 percent holds at the 4-year point. An unexpected reduction in noninvasive cancers also was seen.

Dr. Wickerham stated that these results have been updated through 7 years of followup and, despite unblinding and in some cases crossover, there is still a continued and durable benefit for both invasive and noninvasive disease. He noted also that a durable benefit in NSABP treatment trials where there were reductions in opposite breast cancer now go out to 20 years. Detrimental events included endometrial cancer and thromboembolic events. These were clearly a factor in the acceptability of tamoxifen for this indication. Although the drug has FDA approval as well as endorsement from various societies and organizations, the use of tamoxifen for prevention has not been overwhelming.

Next, Dr. Wickerham described how the Multiple Outcome of Raloxifene (MORE) trial led to the design of NSABP’s P-2 STAR trial.

Raloxifene, another selective estrogen receptor modulator (SERM), is approved in this country for the treatment and prevention of osteoporosis. The results of the MORE trial for postmenopausal women with osteoporosis were announced at the same ASCO plenary session in 1998 where BCPT-P1 results were announced. Women in the raloxifene-treated group demonstrated a 72 percent reduction in invasive breast cancer compared with the placebo group, with no excess of endometrial cancer. This was a group of women with histories of osteoporosis, however, not a group at known increased risk for breast cancer. MORE was a fracture prevention trial, but it did lead to the design of NSABP’s STAR, which studied risk-eligible women based on the Gail score, and only postmenopausal women. Patients were assigned to either tamoxifen and its proven benefits or the promising results from raloxifene as shown in the MORE trial. The objectives were to evaluate the effect of raloxifene versus tamoxifen in reducing the incidence of primary invasive breast cancer. Secondary endpoints included the evaluation of noninvasive


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