###  Metastatic Breast Cancer

#### Premenopausal Women (Tamoxifen Citrate vs. Ablation)

Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared tamoxifen to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the three studies, the hazard ratio for death (tamoxifen/ovarian ablation) was 1.00 with 2-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving tamoxifen, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during tamoxifen therapy responded to subsequent ovarian ablation.

#### Male Breast Cancer

Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with tamoxifen citrate have shown that tamoxifen is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to tamoxifen which constitutes a 50% objective response rate.

###  Adjuvant Breast Cancer

#### Overview

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10 year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant tamoxifen using doses of 20 to 40 mg/day for 1 to 5+ years. Twenty-five percent of patients received one year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing tamoxifen to no adjuvant therapy and 42% were entered into trials comparing tamoxifen in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node-positive disease and 46% had node-negative disease.

Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for tamoxifen vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for tamoxifen vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for tamoxifen vs. 64.3% for control (logrank 2p < 0.00001).

The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of tamoxifen, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001).

Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of tamoxifen on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective.

#### Anastrozole Adjuvant ATAC Trial - Study of Anastrozole Compared to Tamoxifen for Adjuvant Treatment of Early Breast Cancer

An anastrozole adjuvant trial was conducted in 9,366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of these two treatments for 5 years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen therapy alone in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. Please refer to CLINICAL PHARMACOLOGY: Special Populations: Drug-Drug Interactions, PRECAUTIONS: Laboratory Tests, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS sections for safety information from this trial. Please refer to the full prescribing information for ARIMIDEX®† (anastrozole) 1 mg Tablets for additional information on this trial.

Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p = 0.0127] in the anastrazole arm compared to the tamoxifen arm.

#### Node-Positive

##### Individual Studies

Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when tamoxifen was added to adjuvant cytotoxic chemotherapy. In the Hubay study, tamoxifen was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, tamoxifen was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).

In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50 to 59 years, only women with both estrogen- and progesterone-receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen- and progesterone-receptor levels less than 10 fmol. In women aged 60 to 70 years, there was a trend toward a beneficial effect of tamoxifen without any clear relationship to estrogen- or progesterone-receptor status.

Three prospective studies (ECOG-1178, Toronto, NATO) using tamoxifen adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.

#### Node-Negative

##### Individual Studies

NSABP B-14, a prospective, double-blind, randomized study, compared tamoxifen to placebo in women with axillary node-negative, estrogen receptor positive (≥ 10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After 5 years of treatment, there was a significant improvement in disease-free survival in women receiving tamoxifen. This benefit was apparent both in women under age 50 and in women at or beyond age 50.

One additional randomized study (NATO) demonstrated improved disease-free survival for tamoxifen compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of tamoxifen appeared to be independent of estrogen receptor status.

#### Duration of Therapy

In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy.

In the NSABP B-14 trial, in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5-year period were offered rerandomization to an additional 5 years of tamoxifen or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of tamoxifen were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of tamoxifen (p = 0.003). Overall survivals were 96% and 94%, respectively (p = 0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit.

A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the 5 year group and 61% in the indefinite group, with 6.2 years median follow-up (HR = 1.27, 95% CI 0.87 to 1.85).

In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant tamoxifen 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5 year tamoxifen group, compared with 74% among corresponding patients in the 2 year treatment group (p = 0.03). Disease-free survival at 10 years was 73% in the 5 year group and 67% in the 2 year group (p = 0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant.

#### Contralateral Breast Cancer

The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving tamoxifen compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with tamoxifen of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving tamoxifen were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of tamoxifen reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group.

In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant tamoxifen 40 mg/day for 2 to 5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to tamoxifen 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8 per 1,000 patients in the placebo group compared with 5 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.

###  Ductal Carcinoma in Situ

NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of tamoxifen or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of tamoxifen therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.

In this trial 1,804 women were randomized to receive either tamoxifen or placebo for 5 years: 902 women were randomized to tamoxifen 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months.

The tamoxifen and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis.

For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to tamoxifen (44 cases - tamoxifen, 74 cases - placebo; p = 0.004; relative risk (RR) = 0.57, 95% CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base.

Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

Survival was similar in the placebo and tamoxifen groups. At 5 years from study entry, survival was 97% for both groups.

###  Reduction in Breast Cancer Incidence in High Risk Women

The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of tamoxifen citrate therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (see INDICATIONS AND USAGE). Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of tamoxifen, including: endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and cataract formation and surgery (see WARNINGS).

The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5 year predicted risk of breast cancer of ≥ 1.67% was required for entry into the trial.

In this trial, 13,388 women of at least 35 years of age were randomized to receive either tamoxifen or placebo for 5 years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to tamoxifen (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2.

Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to tamoxifen (86 cases-tamoxifen, 156 cases-placebo; p < 0.00001; relative risk (RR) = 0.56, 95% CI: 0.43 to 0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group ( ≤ 49, 50 to 59, ≥ 60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A nonsignificant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23-tamoxifen, 35-placebo; RR = 0.66; 95% CI: 0.39 to 1.11).

There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61-tamoxifen citrate, 59-placebo; RR = 1.04, 95% CI: 0.73 to 1.49).

No overall difference in mortality (53 deaths in tamoxifen group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (four deaths in tamoxifen group vs. five deaths in placebo group).

Although there was a nonsignificant reduction in the number of hip fractures (nine on tamoxifen, 20 on placebo) in the tamoxifen group, the number of wrist fractures was similar in the two treatment groups (69 on tamoxifen, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving tamoxifen. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, tamoxifen was associated with significant bone loss of the lumbar spine and hip in premenopausal women.

The risks of tamoxifen therapy include endometrial cancer, DVT, PE, stroke, cataract formation, and cataract surgery (see Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the tamoxifen group vs. 14 in the placebo group (RR = 2.48, 95% CI: 1.27 to 4.92). Deep vein thrombosis was observed in 30 women receiving tamoxifen vs. 19 in women receiving placebo (RR = 1.59, 95% CI: 0.86 to 2.98). Eighteen cases of pulmonary embolism were observed in the tamoxifen group vs. six in the placebo group (RR = 3.01, 95% CI: 1.15 to 9.27). There were 34 strokes on the tamoxifen arm and 24 on the placebo arm (RR = 1.42, 95% CI: 0.82 to 2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking tamoxifen vs. 483 women receiving placebo (RR = 1.13, 95% CI: 1.00 to 1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking tamoxifen vs. 129 women receiving placebo (RR = 1.51, 95% CI: 1.21 to 1.89) (see WARNINGS).

Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1,000 women per year for the placebo and tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other coexisting risk factors, for women who developed breast cancer. The 5 year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit (see INDICATIONS AND USAGE).

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

Interim results from two 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 one 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 (eight noninvasive, four 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 tamoxifen 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. Tamoxifen 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 prestudy 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. Tamoxifen 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 tamoxifen 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 tamoxifen (see BOXED WARNING), continued monitoring of McCune-Albright patients treated with tamoxifen for long-term uterine effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy in girls have not been established.