Endometrial Cancer and Uterine Sarcoma

An increased incidence of uterine malignancies (endometrial adenocarcinoma and uterine sarcoma), including fatal cases, has been reported with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen with tamoxifen are classified as adenocarcinoma of the endometrium; however, uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. Uterine sarcoma was generally associated with a higher FIGO stage (III/IV) at diagnosis, poor prognosis, and short survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥2 years) of tamoxifen than non-users.

Promptly evaluate any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding. Patients receiving or who have previously received tamoxifen should have annual gynecological examinations. Advise patients to promptly inform a healthcare provider if they experience any abnormal gynecological symptoms (e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure). There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen is beneficial.

In a review of long-term data (median length of total follow-up was 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and uterine sarcomas was increased in women taking tamoxifen.

• During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV].
• During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively).
• Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and 1 patient randomized to placebo (FIGO IA); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the 1 patient randomized to placebo had a MMMT.
• A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in 5 other NSABP clinical trials.

In the NSABP P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women who had not undergone hysterectomy.

Non-Malignant Effects on the Uterus

An increased incidence of endometrial changes including hyperplasia and polyps has been reported with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the partial estrogenic effect of tamoxifen. There have been reports of endometriosis and uterine fibroids in women receiving tamoxifen. Ovarian cysts have also been observed in premenopausal patients with advanced breast cancer who have been treated with tamoxifen. Tamoxifen has been reported to cause menstrual irregularity or amenorrhea.

Liver Cancer

In the Swedish Breast Cancer Cooperative Group trial using adjuvant tamoxifen 40 mg per day (two times the recommended dosage) for 2 to 5 years, 3 cases of liver cancer were reported in the tamoxifen-treated group versus 1 case in the observation group [see Clinical Studies (14.2)]. One case of liver cancer was reported in NSABP P-1 (women at high risk for breast cancer) in a participant randomized to tamoxifen [see Clinical Studies (14.4)].

Hepatocellular carcinoma has been observed in animals receiving tamoxifen [see Nonclinical Toxicology (13.1)].

Non-Malignant Effects on the Liver

Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. Some of these serious cases included fatalities. In most reported cases, the relationship to tamoxifen is uncertain. However, some positive rechallenges and dechallenges have been reported. Monitor liver function periodically.

In the NSABP P-1 trial, grade 3 to 4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on tamoxifen). Serum lipids were not systematically collected.

Adverse Reactions in Patients with Metastatic Breast Cancer

In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction was hot flashes. Other adverse reactions which were seen less commonly are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness.

Increased bone, tumor pain and local disease flare have occurred. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occurred, the bone pain or disease flares were seen shortly after starting tamoxifen and generally subsided rapidly.

Adverse Reactions in Adjuvant Breast Cancer

In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen 20 mg per day or placebo following primary surgery [see Clinical Studies (14.2)]. Table 2 presents the most common adverse reactions (mean follow-up of approximately 6.9 years) that were more common on tamoxifen than placebo.

In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial [see Clinical Studies (14.2)], tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen showed a higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the two treatment groups with the exception of thrombocytopenia, where the incidence for tamoxifen was 10% vs. 3% for placebo.

In other adjuvant studies [the Toronto study and Tamoxifen Adjuvant Trial Organization (NATO)], women received either tamoxifen or no therapy [see Clinical Studies (14.2)]. In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group.

Adverse Reactions in Ductal Carcinoma in Situ

The types and frequency of adverse reactions in the NSABP B-24 trial in women with DCIS were consistent with those observed in the other adjuvant trials conducted with tamoxifen [see Clinical Studies (14.3)].

Adverse Reactions in Women at High Risk for Breast Cancer

In the NSABP P-1 trial, there was an increase in five serious adverse reactions in the tamoxifen group [see Warnings and Precautions (5.1, 5.2, and 5.8) and Clinical Studies (14.4)]:

• endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group);
• pulmonary embolism (18 cases in the tamoxifen group vs. 6 in the placebo group);
• deep vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group);
• stroke (34 cases in the tamoxifen group vs. 24 in the placebo group);
• cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group), and
• cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group).

Table 5 presents the adverse reactions observed in NSABP P-1 by treatment arm. Only adverse reactions more common on tamoxifen than placebo are shown.

In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively, withdrew from the trial for medical reasons including the following: hot flashes (3.1% vs. 1.5%, respectively) and vaginal discharge (0.5% vs. 0.1% respectively).

Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge was severe in 4.5% on placebo and 12.3% on tamoxifen.

SOLTAMOX-related Adverse Reactions

In a single-dose pharmacokinetic study in healthy perimenopausal and postmenopausal women, throat irritation was reported by 3 of 60 evaluable subjects (5%) in the SOLTAMOX treatment group while none of the subjects in the tamoxifen citrate tablet group reported this event. All cases were mild, occurred within an hour after dosing, and resolved within 24 hours.

Men with Metastatic Breast Cancer

Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. In oligospermic males treated with tamoxifen, LH, FSH, testosterone, and estrogen levels were elevated, with no reported associated clinical changes.

Anastrozole

The combination of anastrozole and tamoxifen did not demonstrate any benefit when compared to tamoxifen alone and should be avoided in all patients [see Clinical Studies (14.2)]. In the ATAC trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced the anastrozole plasma concentration by 27% compared to that achieved with anastrozole alone. The tamoxifen concentration was not altered [see Clinical Pharmacology (12.3)].

Letrozole

The concomitant use of letrozole with tamoxifen is not recommended because the efficacy of the combination in the adjuvant treatment of breast cancer has not been established. Tamoxifen reduced the plasma concentration of letrozole by 38% when these drugs were co-administered [see Clinical Pharmacology (12.3)].

Risk Summary

SOLTAMOX can cause fetal harm when administered to a pregnant woman. There are no adequate and well- controlled studies of tamoxifen in pregnant women. There are limited postmarketing reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women taking tamoxifen. In a primate model administration of tamoxifen at doses 2 times higher than the maximum recommended human dose resulted in spontaneous abortion. In rat and rabbit studies, doses of tamoxifen less than or equal to human doses resulted in increased embryotoxicity, abortions, and altered learning behaviors. Additionally, rodent models showed reproductive tract changes often associated with DES in offspring of both sexes [see Data]. Advise pregnant women of the potential risk to a fetus, including the potential long-term risk of a DES-like syndrome.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Risk Summary

There is no information regarding the presence of tamoxifen or its metabolites in human milk or its effects on the breastfed infant. Additional information from juvenile animal studies suggests a potential for serious long- term adverse effects for breastfed infants exposed to tamoxifen through breast milk [see Use in Specific Populations (8.4)]. Because of the potential for serious adverse reactions in breastfed infants from tamoxifen, advise a woman not to breastfeed during treatment with SOLTAMOX and for 3 months following the last dose.

Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of tamoxifen on established milk production is unknown.

Pregnancy Testing

A negative pregnancy test should be confirmed in females of reproductive potential before initiation of SOLTAMOX therapy.

Contraception

Infertility

Tamoxifen Use in McCune-Albright Syndrome

The safety and effectiveness of SOLTAMOX for the treatment of girls with McCune-Albright syndrome, including long-term effects, have not been established.

A single, uncontrolled multicenter trial of tamoxifen 20 mg once a day was conducted in a heterogeneous 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 (defined as the ratio of bone age change and chronological age); individual responses with regard to this endpoint were highly heterogeneous. Linear growth rate (height velocity) 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 to tamoxifen 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, continued monitoring of McCune-Albright patients treated with tamoxifen for long-term uterine effects is recommended.

Pharmacokinetics in Pediatric Patients

The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study of tamoxifen in treating McCune-Albright syndrome. Clearance (CL/F), adjusted for body weight, in female pediatric patients was approximately 2.3-fold higher than in adult female breast cancer patients. In the youngest cohort of female pediatric patients (2 to 6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7 to 10.9 year olds), CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients.

In pediatric patients, an average steady-state peak plasma concentration (Css, max) and AUC were 187 ng/mL and 4,110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after dosing.

Animal Data

Direct neonatal exposure of tamoxifen to mice and rats produced: 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to DES) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis.

Ductal Carcinoma in Situ

In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. This subset is too small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were comparable to those of younger women enrolled in this trial. No overall differences in tolerability were observed between older and younger patients.

Reduction in Breast Cancer Incidence in Women at High Risk

In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets. A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger patients.

Absorption and Distribution

Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N- desmethyl tamoxifen, the major metabolite, is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67 to 183 ng/mL) for tamoxifen and 336 ng/mL (range 148 to 654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71 to 183 ng/mL) and 353 ng/mL (range 152 to 706 ng/mL), respectively. The steady-state plasma concentrations of endoxifen and 4-hydroxytamoxifen are 29.1 (95% CI 24.6 to 33.6) and 3.7 (95% CI 3.3 to 4.1) ng/mL, respectively. After initiation of therapy, steady-state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg tamoxifen tablets given twice a day vs. a 20 mg tamoxifen tablet given once daily, the 20 mg tamoxifen tablet was bioequivalent to the 10 mg tamoxifen tablets.

A pharmacokinetic study was performed in healthy perimenopausal and postmenopausal female subjects to evaluate the bioavailability of SOLTAMOX (n=30) in comparison with the commercially available tamoxifen citrate tablets (n=33) under fasting conditions. A third arm evaluated the effect of food on SOLTAMOX (n=16). The rate and extent of absorption of SOLTAMOX was found to be bioequivalent to that of tamoxifen citrate tablets under fasting conditions. There was no difference in bioavailability (Cmax and AUC) of SOLTAMOX oral solution between fed and fasting states, and therefore SOLTAMOX can be given without regard to meals.

Metabolism

Tamoxifen is extensively metabolized by CYP450 enzymes, including CYP3A, CYP2D6, CYP2C9, CYP2C19, and CYP2B6. N-desmethyltamoxifen, formed predominantly by CYP3A, is the major metabolite found in plasma. The pharmacological activity of N-desmethyltamoxifen is similar to that of tamoxifen. Endoxifen and 4-hydroxytamoxifen, identified as minor metabolites, have 100-fold greater affinity for the estrogen receptor and 30 to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. The polymorphic enzyme CYP2D6 is involved in the formation of endoxifen and 4-hydroxytamoxifen, and it is the key enzyme that catalyzes the formation of endoxifen from N-desmethyltamoxifen. Endoxifen concentrations may differ among patients because of various CYP2D6 genotypes [see Clinical Pharmacology (12.5)]. Phase 2 enzymes, such as SULT1A1, UGT2B7, and UGT1A4, are associated with tamoxifen clearance from plasma.

Excretion

Studies in women receiving 20 mg of 14C tamoxifen showed that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks, with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

Specific Populations

The effects of age, gender, and race on the pharmacokinetics of tamoxifen in adults have not been determined. Some data are available on tamoxifen pharmacokinetics in children [see Use in Specific Populations (8.4)]. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.

Drug-Drug Interactions

Premenopausal Women

Three prospective, randomized studies compared another formulation of 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 3 studies, the hazard ratio (HR) for death (tamoxifen/ovarian ablation) was 1.00 with two-sided 95% confidence intervals (CI) of 0.73 to 1.37. Limited number of patients with disease progression during tamoxifen therapy responded to subsequent ovarian ablation.

Men with Metastatic Breast Cancer

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

Pooled Studies of Adjuvant Treatment of Breast Cancer

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, 1995, 1998 and 2011.

The 10-year outcome data were reported in 1998 for 36,689 women in 55 randomized trials of another formulation of adjuvant tamoxifen using doses of 20 to 40 mg per day for 1 to 5+ years. Twenty-five percent of patients received 1 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/mg), and 31% were ER-unknown. Among 29,441 patients with ER-positive or ER-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.

In women with ER-positive or ER-unknown breast cancer:

• With positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for tamoxifen vs. 50.5% for control (log-rank 2p <0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen vs. 44.5% for control (log-rank 2p <0.00001).
• With negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for tamoxifen vs. 73.3% for control (log-rank 2p <0.00001). The recurrence-free rate at 10 years was 79.2% for tamoxifen vs. 64.3% for control (log-rank 2p <0.00001).
• Who received 1 year or less, 2 years, or about 5 years of tamoxifen, the proportional reductions in mortality were 12%, 17%, and 26%, respectively (2p <0.003). The corresponding reductions in breast cancer recurrence were 21%, 29%, and 47% (2p <0.00001).

Results in patients with ER-poor breast cancer

• 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% (not significant).

The effects of about 5 years of tamoxifen on recurrence and mortality were similar regardless of age and concurrent chemotherapy.

The 15-year outcome data were reported in 2011 for 21,457 women in 20 randomized trials, and continued to confirm the earlier overview results. Five-year treatment with adjuvant tamoxifen reduced the 15-year risks of breast cancer recurrence and death.

Node-positive: Individual Studies

Two studies [Hubay and National Surgical Adjuvant Breast and Bowel Project (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 another formulation of 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 and fluorouracil.

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 survival results were poorer in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60 to 70 years, there was an improvement in disease-free survival with tamoxifen without any clear relationship to estrogen or progesterone receptor status.

Three prospective studies (ECOG-1178, Toronto, and Tamoxifen Adjuvant Trial Organization (NATO)] using another formulation of tamoxifen adjuvantly as a single agent demonstrated 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 another formulation of tamoxifen to placebo as adjuvant therapy in women with axillary node-negative, estrogen-receptor positive (≥10 fmol/mg cytosol protein) breast cancer (following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five 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 another formulation of 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

Available data supported 5 years of adjuvant tamoxifen therapy for patients with breast cancer. 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. Although results of the NSABP B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit, a subsequent report of the ATLAS trial suggest that continuing tamoxifen to 10 years further reduced recurrence and mortality.

Contralateral Breast Cancer

The incidence of contralateral breast cancer was reduced in breast cancer patients (premenopausal and postmenopausal) receiving adjuvant 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 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% (not significant), 26% (2p = 0.004) and 47% (2p <0.00001), respectively. The reduction in the incidence of contralateral breast cancer was significant with 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 to 3.9 per 1,000 patients in the tamoxifen group.

In a Swedish Breast Cancer Cooperative Group trial where another formulation of adjuvant tamoxifen was given at a dose of 40 mg per day (two times the recommended dosage) 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 per day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p <0.01). The annual rate of contralateral breast cancer was 8.0 per 1,000 patients in the placebo group compared to 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.

Anastrozole Adjuvant Trial (ATAC: Arimidex, Tamoxifen, Alone or in Combination) – Study of Anastrozole Compared to Tamoxifen for Adjuvant Treatment of Early Breast Cancer

A 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, another formulation of 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 to tamoxifen alone in all patients, as well as in the hormone receptor-positive subpopulation. The combination treatment arm was discontinued from the trial [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Refer to the full prescribing information for anastrozole tablets for additional information on this trial.

Breast Cancer Prevention Trial (NSABP P-1)

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

The Breast Cancer Assessment Tool1 (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 five years. The median duration of treatment was 3.5 years. Follow-up data were 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.

Italian Tamoxifen Prevention Trial and the Royal Marsden Trial

Interim results from two additional trials examining the effects of another formulation of tamoxifen in reducing breast cancer incidence are summarized below.

In the Italian Tamoxifen Prevention trial, 5,408 women without any specific risk factors for breast cancer and who had undergone a total hysterectomy were randomized to receive 20 mg tamoxifen or placebo for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Hormone replacement therapy (HRT) was used in 14% of participants. The trial closed because of 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 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. Tamoxifen is not approved for women who are at low risk for breast cancer.

The Royal Marsden Trial (RMT) was also reported as an interim analysis. The RMT was undertaken as a feasibility study of whether larger scale trials could be mounted. Twenty-four hundred and seventy-one women were enrolled, based on 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-negative 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 two 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 frequencies of these events were consistent with the data observed in the NSABP P-1 trial.