Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor size, nodal status, ER status. NOLVADEX decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors.

Table 4. Characteristics of Breast Cancer in NSABP P-1 Trial

Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of tamoxifen in reducing breast cancer incidence have been reported.

The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and 70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5408 women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After 46 months of follow-up there were 22 breast cancers in women on placebo and 19 in women on tamoxifen. Although no decrease in breast cancer incidence was observed, there was a trend for a reduction in breast cancer among women receiving protocol therapy for at least 1 year (19-placebo, 11- tamoxifen). The small numbers of participants along with the low level of risk in this otherwise healthy group precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of breast cancer.

The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT was begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was subsequently extended to a pilot trial to accrue additional participants to further assess the safety of tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986 and 1996; they were selected on the basis of a family history of breast cancer. HRT was used in 40% of participants. In this trial, with a 70 month median follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm) were observed among women on tamoxifen and placebo, respectively. Patients in this trial were younger than those in the NSABP P-1 trial and may have been more likely to develop ER (-) tumors, which are unlikely to be reduced in number by tamoxifen therapy. Although women were selected on the basis of family history and were thought to have a high risk of breast cancer, few events occurred, reducing the statistical power of the study. These factors are potential reasons why the RMT may not have provided an adequate assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer.

In these trials, an increased number of cases of deep vein thrombosis, pulmonary embolus, stroke, and endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency of events was consistent with the safety data observed in the NSABP P-1 trial.

McCune-Albright Syndrome

A single, uncontrolled multicenter trial of NOLVADEX 20 mg once a day was conducted in a heterogenous group of girls with McCune-Albright Syndrome and precocious puberty manifested by physical signs of pubertal development, episodes of vaginal bleeding and/or advanced bone age (bone age of at least 12 months beyond chronological age). Twenty-eight female pediatric patients, aged 2 to 10 years, were treated for up to 12 months. Effect of treatment on frequency of vaginal bleeding, bone age advancement, and linear growth rate was assessed relative to prestudy baseline. NOLVADEX treatment was associated with a 50% reduction in frequency of vaginal bleeding episodes by patient or family report (mean annualized frequency of 3.56 episodes at baseline and 1.73 episodes on-treatment). Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6-month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Not all patients improved on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. NOLVADEX therapy was associated with a reduction in mean rate of increase of bone age. Individual responses with regard to bone age advancement were highly heterogeneous. Linear growth rate was reduced during the course of NOLVADEX treatment in a majority of patients (mean change of 1.68 cm/year relative to baseline; change from 7.47 cm/year at baseline to 5.79 cm/year on study). This change was not uniformly seen across all stages of bone maturity; all recorded response failures occurred in patients with bone ages less than 7 years at screening.

Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with NOLVADEX (see BOXED WARNING), continued monitoring of McCune-Albright patients treated with NOLVADEX for long-term uterine effects is recommended. The safety and efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of NOLVADEX therapy in girls have not been established.

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