Breast cancer: The European and The US studies: interim analyses

A somewhat different study population participated in the two other tamoxifen studies, a factor that, say some authorities, may help account for the very different results seen.4,5 In a Scottish study, 2,471 women with strong family histories of breast cancer were randomized to receive either tamoxifen, 20 mg per day, or placebo, and the trial was planned to last 8 years. By the time of the interim analysis, at 70 months, the investigators believed they would be more than 90% likely to be capable of detecting a 50% reduction in cancer incidence, as was seen in the Breast Cancer Prevention Trial, if indeed their patient population was responding in a similar fashion.

This was not the case, however. "From the 47% reduction in the frequency of contralateral new breast cancers in women on adjuvant tamoxifen after treatment of primary breast cancer, we anticipated that giving tamoxifen to healthy high-risk women would produce at least an equivalent result," the investigators wrote. "We are therefore surprised to see no overall reduction in the occurrence of breast cancer in participants randomised in our trial to tamoxifen." A total of 34 and 36 cases of new breast cancer was seen among the tamoxifen-treated women and the placebo group, respectively.

In the Italian study, a group of 5,408 women who had undergone hysterectomy were randomized to receive tamoxifen, 20 mg/d or a placebo, and the trial was intended to last 5 years. Similar statistically insignificant results were seen in a preliminary analysis at 46 months, with 19 and 22 cases in the tamoxifen and placebo groups, respectively. No deaths were seen in either group, and these authors particularly emphasized that much longer follow-up will be needed, not only to achieve sufficient power for a more valid analysis, but also to evaluate the effects of tamoxifen on mortality rates.

Both groups of investigators and other authorities have advanced a number of possible explanations for the discrepancies in their results:

Age at entry. In the British study, the mean age was 47 years and two thirds of participants were premenopausal. The mean age in the Italian study was 51 years.

Family history. In the Breast Cancer Prevention Trial, 76% of participants had a first-degree relative with breast cancer, compared with 96% in the British study and only 15% in the Italian study. The effect of tamoxifen on breast cancers that may have a genetic component is particularly difficult to determine, and many experts believe this factor may be the most important aspect of the lack of efficacy seen in the UK study.

Concurrent HRT. Unlike the Breast Cancer Prevention Trial, in the two European studies, concurrent hormone replacement therapy (HRT) was permitted. In the UK study, for example, 26% of participants were on HRT.

Compliance. The Italian study was characterized by poor compliance, with 26% of participants dropping out of the trial.