European Tamoxifen Prevention Trials Contradict BCPT

LONDON--Interim analyses of two randomized European trials of tamoxifen (Nolvadex) prophylaxis in healthy women have failed to show a significant reduction in the incidence of breast cancer, in contrast to the US Breast Cancer Prevention Trial (BCPT), which showed a 45% reduction with tamoxifen.

The two European reports both appeared in The Lancet (352:93-97, 98-101, 1998), along with a commentary by Dr. Kathleen I. Pritchard, of the University of Toronto, in which she suggested that the discrepancy may stem largely from differences in patient populations.

Trevor Powles, MD, of the Royal Marsden Hospital, reported on 2,471 women with a family history of breast cancer randomized to tamoxifen, 20 mg/d, or placebo for 8 years. With a median follow-up of 70 months, the researchers have found no difference in overall breast cancer frequency (34 cases in the tamoxifen arm vs 36 for placebo).

The trial has a 90% power to detect a significant 50% reduction in breast cancer frequency at the 5% level. Compliance was good, he said, and unlikely to be a cause of the negative result.

More likely causes of the discrepancy are the differences in eligibility criteria, with entry into the London trial based predominantly on a strong family history and thus a strong likelihood of including patients with an inherited BRCA1 mutation. In contrast, the BCPT entry criteria were based primarily on nongenetic risk factors. "Estrogen promotion, which we would be expecting tamoxifen to oppose, may not be important in the genesis of clinical breast cancer in high-risk gene carriers," Dr. Powles said.

A further issue is the duration of follow-up: an average of 3½ years for the BCPT, compared with a median of nearly 6 years in the London trial. "The relatively early frequency data in the NSABP trial would largely reflect treatment of occult primary cancers, rather than prevention by blocking estrogen promotion of a transformed cell into an active cancer," he said.

Dr. Powles said that treatment and follow-up in the London trial continue, and that the data will eventually contribute to a metaanalysis of all tamoxifen chemoprevention trials.

Italian Study Results

The Italian Tamoxifen Prevention Study included 5,408 hysterectomized women (at low to normal breast cancer risk) randomized to tamoxifen 20 mg/d or placebo for 5 years. At median follow-up of 46 months, there is no difference in breast cancer frequency between placebo (22 cases) and tamoxifen (19 cases).

The trial did have a problem with compliance, with 26% of patients dropping out of the study, most within the first year after randomization. There was a trend toward a reduction in breast cancer incidence among those women who took tamoxifen for more than a year (11 cases), compared with placebo recipients who stayed on trial that long (19 cases).

As with the London trial, treatment and follow-up continue, said Dr. Umberto Veronesi, of the European Institute of Oncology, Milan. The power of the study at present is low, he said, "and it is possible that the finding will be overturned by continued follow-up," especially among those women who stay on treatment for more than a year. The Italian group also anticipates taking part in a pooled analysis with other trials.

Dr. Pritchard noted that the Italian trial--in addition to compliance problems and enrollment of patients who were not at high risk--had far fewer women age 60 and above (12%) than the BCPT (30%). This age group had slightly greater benefits from tamoxifen in the BCPT, and also are more likely to have ER-positive tumors, which are more susceptible to tamoxifen’s effects. She pointed out that the London study included more younger women than either of the other studies (62% under age 50 vs about 40% in the BCPT and 36% in the Italian trial).

"The seemingly different results may be largely due to a younger population in both trials, to poor compliance in the Veronesi study, and to differences in the populations studied (most importantly, those in risk levels and family history)," she said. Dr. Pritchard emphasized that longer follow-up of completed and current trials is needed. "The decision of the investigators and data monitoring committee of a fourth large tamoxifen preventive trial to keep that trial masked and to continue accruing participants seems wiser day by day," she said, referring to the International Breast Cancer Intervention Study (IBIS) that has now enrolled 4,000 of a targeted 7,000 women.