Tamoxifen Citrate Prescribing Information
Serious and life-threatening events associated with tamoxifen in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see
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 therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (see
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. 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
| Characteristic | Placebo | Tamoxifen | ||
|---|---|---|---|---|
| # | % | # | % | |
| Age (yrs.) | ||||
| 35 to 39 | 184 | 3 | 158 | 2 |
| 40 to 49 | 2,394 | 36 | 2,411 | 37 |
| 50 to 59 | 2,011 | 31 | 2,019 | 31 |
| 60 to 69 | 1,588 | 24 | 1,563 | 24 |
| ≥ 70 | 393 | 6 | 393 | 6 |
| Age at first live birth (yrs.) | ||||
| Nulliparous | 1,202 | 18 | 1,205 | 18 |
| 12 to 19 | 915 | 14 | 946 | 15 |
| 20 to 24 | 2,448 | 37 | 2,449 | 37 |
| 25 to 29 | 1,399 | 21 | 1,367 | 21 |
| ≥ 30 | 606 | 9 | 577 | 9 |
| Race | ||||
| White | 6,333 | 96 | 6,323 | 96 |
| Black | 109 | 2 | 103 | 2 |
| Other | 128 | 2 | 118 | 2 |
| Age at menarche | ||||
| ≥ 14 | 1,243 | 19 | 1,170 | 18 |
| 12 to 13 | 3,610 | 55 | 3,610 | 55 |
| ≤ 11 | 1,717 | 26 | 1,764 | 27 |
| # of first degree relatives with breast cancer | ||||
| 0 | 1,584 | 24 | 1,525 | 23 |
| 1 | 3,714 | 57 | 3,744 | 57 |
| 2+ | 1,272 | 19 | 1,275 | 20 |
| Prior hysterectomy | ||||
| No | 4,173 | 63.5 | 4,018 | 62.4 |
| Yes | 2,397 | 36.5 | 2,464 | 37.7 |
| # of previous breast biopsies | ||||
| 0 | 2,935 | 45 | 2,923 | 45 |
| 1 | 1,833 | 28 | 1,850 | 28 |
| ≥ 2 | 1,802 | 27 | 1,771 | 27 |
| History of atypical hyperplasia in the breast | ||||
| No | 5,958 | 91 | 5,969 | 91 |
| Yes | 612 | 9 | 575 | 9 |
| History of LCIS at entry | ||||
| No | 6,165 | 94 | 6,135 | 94 |
| Yes | 405 | 6 | 409 | 6 |
| 5 year predicted breast cancer risk (%) | ||||
| ≤ 2.00 | 1,646 | 25 | 1,626 | 25 |
| 2.01 to 3.00 | 2,028 | 31 | 2,057 | 31 |
| 3.01 to 5.00 | 1,787 | 27 | 1,707 | 26 |
| ≥ 5.01 | 1,109 | 17 | 1,162 | 18 |
| Total | 6,570 | 100.0 | 6,544 | 100.0 |
Results are shown in
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, 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 (4 deaths in tamoxifen group vs. 5 deaths in placebo group).
Although there was a non-significant reduction in the number of hip fractures (9 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
For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing 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
| TYPE OF EVENT | # OF EVENTS | RATE/1,000 WOMEN/YEAR | 95% CI | |||
|---|---|---|---|---|---|---|
| PLACEBO | TAMOXIFEN | PLACEBO | TAMOXIFEN | RR | LIMITS | |
| Invasive Breast Cancer | 156 | 86 | 6.49 | 3.58 | 0.56 | 0.43 to 0.72 |
| Age ≤ 49 | 59 | 38 | 6.34 | 4.11 | 0.65 | 0.43 to 0.98 |
| Age 50 to 59 | 46 | 25 | 6.31 | 3.53 | 0.56 | 0.35 to 0.91 |
| Age ≥ 60 | 51 | 23 | 7.17 | 3.22 | 0.45 | 0.27 to 0.74 |
| Risk Factors for Breast Cancer History, LCIS | ||||||
| No | 140 | 78 | 6.23 | 3.51 | 0.56 | 0.43 to 0.74 |
| Yes | 16 | 8 | 12.73 | 6.33 | 0.50 | 0.21 to 1.17 |
| History, Atypical Hyperplasia | ||||||
| No | 138 | 84 | 6.37 | 3.89 | 0.61 | 0.47 to 0.80 |
| Yes | 18 | 2 | 8.69 | 1.05 | 0.12 | 0.03 to 0.52 |
| No. First Degree Relatives | ||||||
| 0 | 32 | 17 | 5.97 | 3.26 | 0.55 | 0.30 to 0.98 |
| 1 | 80 | 45 | 5.81 | 3.31 | 0.57 | 0.40 to 0.82 |
| 2 | 35 | 18 | 8.92 | 4.67 | 0.52 | 0.30 to 0.92 |
| ≥ 3 | 9 | 6 | 13.33 | 7.58 | 0.57 | 0.20 to 1.59 |
| 5 Year Predicted Breast Cancer Risk (as calculated by the Gail Model) | ||||||
| ≤ 2.00% | 31 | 13 | 5.36 | 2.26 | 0.42 | 0.22 to 0.81 |
| 2.01 to 3.00% | 39 | 28 | 5.25 | 3.83 | 0.73 | 0.45 to 1.18 |
| 3.01 to 5.00% | 36 | 26 | 5.37 | 4.06 | 0.76 | 0.46 to 1.26 |
| ≥ 5.00% | 50 | 19 | 13.15 | 4.71 | 0.36 | 0.21 to 0.61 |
| DCIS | 35 | 23 | 1.47 | 0.97 | 0.66 | 0.39 to 1.11 |
| Fractures (protocol-specified sites) | 92Two women had hip and wrist fractures | 76 | 3.87 | 3.20 | 0.61 | 0.83 to 1.12 |
| Hip | 20 | 9 | 0.84 | 0.38 | 0.45 | 0.18 to 1.04 |
| WristIncludes Colles' and other lower radius fractures | 74 | 69 | 3.11 | 2.91 | 0.93 | 0.67 to 1.29 |
| Total Ischemic Events | 59 | 61 | 2.47 | 2.57 | 1.04 | 0.71 to 1.51 |
| Myocardial Infarction | 27 | 27 | 1.13 | 1.13 | 1.00 | 0.57 to 1.78 |
| Fatal | 8 | 7 | 0.33 | 0.29 | 0.88 | 0.27 to 2.77 |
| Nonfatal | 19 | 20 | 0.79 | 0.84 | 1.06 | 0.54 to 2.09 |
| AnginaRequiring angioplasty or CABG | 12 | 12 | 0.50 | 0.50 | 1.00 | 0.41 to 2.44 |
| Acute Ischemic SyndromeNew Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization without surgery | 20 | 22 | 0.84 | 0.92 | 1.11 | 0.58 to 2.13 |
| Uterine Malignancies (among women with an intact uterus)Updated long-term follow-up data (median 6.9 years) from NSABP P-1 study added after cut-off for the other information in this table. | 17 | 57 | ||||
| Endometrial Adenocarcinoma | 17 | 53 | 0.71 | 2.20 | ||
| Uterine Sarcoma | 0 | 4 | 0.0 | 0.17 | ||
| StrokeSeven cases were fatal; three in the placebo group and four in the tamoxifen group | 24 | 34 | 1.00 | 1.43 | 1.42 | 0.82 to 2.51 |
| Transient Ischemic Attack | 21 | 18 | 0.88 | 0.75 | 0.86 | 0.43 to 1.70 |
| Pulmonary EmboliThree cases in the tamoxifen group were fatal | 6 | 18 | 0.25 | 0.75 | 3.01 | 1.15 to 9.27 |
| Deep-Vein ThrombosisAll but three cases in each group required hospitalization | 19 | 30 | 0.79 | 1.26 | 1.59 | 0.86 to 2.98 |
| Cataracts Developing on StudyBased on women without cataracts at baseline (6,230 Placebo, 6,199 Tamoxifen) | 483 | 540 | 22.51 | 25.41 | 1.13 | 1.00 to 1.28 |
| Underwent Cataract Surgery | 63 | 101 | 2.83 | 4.57 | 1.62 | 1.18 to 2.22 |
| Underwent Cataract SurgeryAll women (6,707 Placebo, 6,681 Tamoxifen) | 129 | 201 | 5.44 | 8.56 | 1.58 | 1.26 to 1.97 |
| Staging Parameter | Placebo | Tamoxifen | Total |
|---|---|---|---|
| N = 156 | N = 86 | N = 242 | |
Tumor size: | |||
| T1 | 117 | 60 | 177 |
| T2 | 28 | 20 | 48 |
| T3 | 7 | 3 | 10 |
| T4 | 1 | 2 | 3 |
| Unknown | 3 | 1 | 4 |
Nodal status: | |||
| Negative | 103 | 56 | 159 |
| 1 to 3 positive nodes | 29 | 14 | 43 |
| ≥ 4 positive nodes | 10 | 12 | 22 |
| Unknown | 14 | 4 | 18 |
Stage: | |||
| I | 88 | 47 | 135 |
| II: node negative | 15 | 9 | 24 |
| II: node positive | 33 | 22 | 55 |
| III | 6 | 4 | 10 |
| IV | 2One participant presented with a suspicious bone scan but did not have documented metastases. She subsequently died of metastatic breast cancer. | 1 | 3 |
| Unknown | 12 | 3 | 15 |
Estrogen receptor: | |||
| Positive | 115 | 38 | 153 |
| Negative | 27 | 36 | 63 |
| Unknown | 14 | 12 | 26 |
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, 5,408 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 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.
An increased incidence of uterine malignancies has been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥ 2 years) of tamoxifen than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal.
In the NSABP P-1 trial, among participants randomized to tamoxifen there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR = 2.48, 95% CI: 1.27 to 4.92). The 33 cases in participants receiving tamoxifen were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on tamoxifen and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR = 4.50, 95% CI: 1.78 to 13.16). Among women ≤ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR = 0.94, 95% CI: 0.28 to 2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants ≤ 49 randomized to tamoxifen compared to 2 among participants randomized to placebo (RR = 2.21, 95% CI: 0.4 to 12.0). For women ≥ 50 at the time of diagnosis, there were 29 cases among participants randomized to tamoxifen compared to 12 among women on placebo (RR = 2.5, 95% CI: 1.3 to 4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the tamoxifen group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen group occurred in asymptomatic women. Among women receiving tamoxifen the events appeared between 1 and 61 months (average = 32 months) from the start of treatment.
In an updated review of long-term data (median length of total follow-up is 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 rare 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]. Of the patients receiving tamoxifen who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage IB cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. 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). Some patients received postoperative radiation therapy in addition to surgery. 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 1A); 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.
Any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received tamoxifen should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure.
In the 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 with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen to reduce the incidence of breast cancer would be beneficial.
| TYPE OF EVENT | # OF EVENTS | RATE/1,000 WOMEN/YEAR | 95% CI | |||
|---|---|---|---|---|---|---|
| PLACEBO | TAMOXIFEN | PLACEBO | TAMOXIFEN | RR | LIMITS | |
| Invasive Breast Cancer | 156 | 86 | 6.49 | 3.58 | 0.56 | 0.43 to 0.72 |
| Age ≤ 49 | 59 | 38 | 6.34 | 4.11 | 0.65 | 0.43 to 0.98 |
| Age 50 to 59 | 46 | 25 | 6.31 | 3.53 | 0.56 | 0.35 to 0.91 |
| Age ≥ 60 | 51 | 23 | 7.17 | 3.22 | 0.45 | 0.27 to 0.74 |
| Risk Factors for Breast Cancer History, LCIS | ||||||
| No | 140 | 78 | 6.23 | 3.51 | 0.56 | 0.43 to 0.74 |
| Yes | 16 | 8 | 12.73 | 6.33 | 0.50 | 0.21 to 1.17 |
| History, Atypical Hyperplasia | ||||||
| No | 138 | 84 | 6.37 | 3.89 | 0.61 | 0.47 to 0.80 |
| Yes | 18 | 2 | 8.69 | 1.05 | 0.12 | 0.03 to 0.52 |
| No. First Degree Relatives | ||||||
| 0 | 32 | 17 | 5.97 | 3.26 | 0.55 | 0.30 to 0.98 |
| 1 | 80 | 45 | 5.81 | 3.31 | 0.57 | 0.40 to 0.82 |
| 2 | 35 | 18 | 8.92 | 4.67 | 0.52 | 0.30 to 0.92 |
| ≥ 3 | 9 | 6 | 13.33 | 7.58 | 0.57 | 0.20 to 1.59 |
| 5 Year Predicted Breast Cancer Risk (as calculated by the Gail Model) | ||||||
| ≤ 2.00% | 31 | 13 | 5.36 | 2.26 | 0.42 | 0.22 to 0.81 |
| 2.01 to 3.00% | 39 | 28 | 5.25 | 3.83 | 0.73 | 0.45 to 1.18 |
| 3.01 to 5.00% | 36 | 26 | 5.37 | 4.06 | 0.76 | 0.46 to 1.26 |
| ≥ 5.00% | 50 | 19 | 13.15 | 4.71 | 0.36 | 0.21 to 0.61 |
| DCIS | 35 | 23 | 1.47 | 0.97 | 0.66 | 0.39 to 1.11 |
| Fractures (protocol-specified sites) | 92Two women had hip and wrist fractures | 76 | 3.87 | 3.20 | 0.61 | 0.83 to 1.12 |
| Hip | 20 | 9 | 0.84 | 0.38 | 0.45 | 0.18 to 1.04 |
| WristIncludes Colles' and other lower radius fractures | 74 | 69 | 3.11 | 2.91 | 0.93 | 0.67 to 1.29 |
| Total Ischemic Events | 59 | 61 | 2.47 | 2.57 | 1.04 | 0.71 to 1.51 |
| Myocardial Infarction | 27 | 27 | 1.13 | 1.13 | 1.00 | 0.57 to 1.78 |
| Fatal | 8 | 7 | 0.33 | 0.29 | 0.88 | 0.27 to 2.77 |
| Nonfatal | 19 | 20 | 0.79 | 0.84 | 1.06 | 0.54 to 2.09 |
| AnginaRequiring angioplasty or CABG | 12 | 12 | 0.50 | 0.50 | 1.00 | 0.41 to 2.44 |
| Acute Ischemic SyndromeNew Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization without surgery | 20 | 22 | 0.84 | 0.92 | 1.11 | 0.58 to 2.13 |
| Uterine Malignancies (among women with an intact uterus)Updated long-term follow-up data (median 6.9 years) from NSABP P-1 study added after cut-off for the other information in this table. | 17 | 57 | ||||
| Endometrial Adenocarcinoma | 17 | 53 | 0.71 | 2.20 | ||
| Uterine Sarcoma | 0 | 4 | 0.0 | 0.17 | ||
| StrokeSeven cases were fatal; three in the placebo group and four in the tamoxifen group | 24 | 34 | 1.00 | 1.43 | 1.42 | 0.82 to 2.51 |
| Transient Ischemic Attack | 21 | 18 | 0.88 | 0.75 | 0.86 | 0.43 to 1.70 |
| Pulmonary EmboliThree cases in the tamoxifen group were fatal | 6 | 18 | 0.25 | 0.75 | 3.01 | 1.15 to 9.27 |
| Deep-Vein ThrombosisAll but three cases in each group required hospitalization | 19 | 30 | 0.79 | 1.26 | 1.59 | 0.86 to 2.98 |
| Cataracts Developing on StudyBased on women without cataracts at baseline (6,230 Placebo, 6,199 Tamoxifen) | 483 | 540 | 22.51 | 25.41 | 1.13 | 1.00 to 1.28 |
| Underwent Cataract Surgery | 63 | 101 | 2.83 | 4.57 | 1.62 | 1.18 to 2.22 |
| Underwent Cataract SurgeryAll women (6,707 Placebo, 6,681 Tamoxifen) | 129 | 201 | 5.44 | 8.56 | 1.58 | 1.26 to 1.97 |
Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.
Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer.
The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.
Tamoxifen citrate tablets are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy.
For patients with breast cancer, the recommended daily dose is 20 to 40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening).
In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit (see
Tamoxifen citrate is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.
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 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. 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 citrate tablets given twice a day vs. a 20 mg tamoxifen citrate tablet given once daily, the 20 mg tamoxifen citrate tablet was bioequivalent to the 10 mg tamoxifen citrate tablets.
Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.
Studies in women receiving 20 mg of14C tamoxifen have shown 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.
The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.
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 designed to evaluate the safety, efficacy, and pharmacokinetics of tamoxifen in treating McCune-Albright syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data.
In pediatric patients, an average steady-state peak plasma concentration (Css, max) and AUC were of 187 ng/mL and 4,110 ng hr/mL, respectively, and Css, maxoccurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3 fold higher than in 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.
Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmaxby 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
In the anastrozole adjuvant trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see
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 3 studies, the hazard ratio for death (tamoxifen/ovarian ablation) was 1.00 with two-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.
Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with tamoxifen 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.
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 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/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.
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
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 anastrozole arm compared to the tamoxifen arm.
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 "lowdose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, tamoxifen was added to melphalan [Lphenylalanine 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 age 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.
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 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 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.
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 five-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.
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 8.0 per 1,000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.
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 citrate 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
| Type of Event | Lumpectomy, radiotherapy, and placebo | Lumpectomy, radiotherapy, and tamoxifen | RR | 95% CI limits | ||
|---|---|---|---|---|---|---|
| No. of events | Rate per 1,000 women per year | No. of events | Rate per 1,000 women per year | |||
Invasive breast cancer (Primary endpoint) | 74 | 16.73 | 44 | 9.60 | 0.57 | 0.39 to 0.84 |
| Ipsilateral | 47 | 10.61 | 27 | 5.90 | 0.56 | 0.33 to 0.91 |
| Contralateral | 25 | 5.64 | 17 | 3.71 | 0.66 | 0.33 to 1.27 |
| Side undetermined | 2 | -- | 0 | -- | -- | |
Secondary Endpoints | ||||||
| DCIS | 56 | 12.66 | 41 | 8.95 | 0.71 | 0.46 to 1.08 |
| Ipsilateral | 46 | 10.40 | 38 | 8.29 | 0.88 | 0.51 to 1.25 |
| Contralateral | 10 | 2.26 | 3 | 0.65 | 0.29 | 0.05 to 1.13 |
| All Breast Cancer Events | 129 | 29.16 | 84 | 18.34 | 0.63 | 0.47 to 0.83 |
| All ipsilateral events | 96 | 21.70 | 65 | 14.19 | 0.65 | 0.47 to 0.91 |
| All contralateral events | 37 | 8.36 | 20 | 4.37 | 0.52 | 0.29 to 0.92 |
| Deaths | 32 | 28 | ||||
| Uterine MalignanciesUpdated follow-up data (median 8.1 years) | 4 | 9 | ||||
| Endometrial Adenocarcinoma | 4 | 0.57 | 8 | 1.15 | ||
| Uterine Sarcoma | 0 | 0.0 | 1 | 0.14 | ||
| Second primary malignancies (other than endometrial and breast) | 30 | 29 | ||||
| Stroke | 2 | 7 | ||||
| Thromboembolic events (DVT, PE) | 5 | 15 | ||||
Survival was similar in the placebo and tamoxifen groups. At 5 years from study entry, survival was 97% for both groups.
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 therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (see
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. 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
| Characteristic | Placebo | Tamoxifen | ||
|---|---|---|---|---|
| # | % | # | % | |
| Age (yrs.) | ||||
| 35 to 39 | 184 | 3 | 158 | 2 |
| 40 to 49 | 2,394 | 36 | 2,411 | 37 |
| 50 to 59 | 2,011 | 31 | 2,019 | 31 |
| 60 to 69 | 1,588 | 24 | 1,563 | 24 |
| ≥ 70 | 393 | 6 | 393 | 6 |
| Age at first live birth (yrs.) | ||||
| Nulliparous | 1,202 | 18 | 1,205 | 18 |
| 12 to 19 | 915 | 14 | 946 | 15 |
| 20 to 24 | 2,448 | 37 | 2,449 | 37 |
| 25 to 29 | 1,399 | 21 | 1,367 | 21 |
| ≥ 30 | 606 | 9 | 577 | 9 |
| Race | ||||
| White | 6,333 | 96 | 6,323 | 96 |
| Black | 109 | 2 | 103 | 2 |
| Other | 128 | 2 | 118 | 2 |
| Age at menarche | ||||
| ≥ 14 | 1,243 | 19 | 1,170 | 18 |
| 12 to 13 | 3,610 | 55 | 3,610 | 55 |
| ≤ 11 | 1,717 | 26 | 1,764 | 27 |
| # of first degree relatives with breast cancer | ||||
| 0 | 1,584 | 24 | 1,525 | 23 |
| 1 | 3,714 | 57 | 3,744 | 57 |
| 2+ | 1,272 | 19 | 1,275 | 20 |
| Prior hysterectomy | ||||
| No | 4,173 | 63.5 | 4,018 | 62.4 |
| Yes | 2,397 | 36.5 | 2,464 | 37.7 |
| # of previous breast biopsies | ||||
| 0 | 2,935 | 45 | 2,923 | 45 |
| 1 | 1,833 | 28 | 1,850 | 28 |
| ≥ 2 | 1,802 | 27 | 1,771 | 27 |
| History of atypical hyperplasia in the breast | ||||
| No | 5,958 | 91 | 5,969 | 91 |
| Yes | 612 | 9 | 575 | 9 |
| History of LCIS at entry | ||||
| No | 6,165 | 94 | 6,135 | 94 |
| Yes | 405 | 6 | 409 | 6 |
| 5 year predicted breast cancer risk (%) | ||||
| ≤ 2.00 | 1,646 | 25 | 1,626 | 25 |
| 2.01 to 3.00 | 2,028 | 31 | 2,057 | 31 |
| 3.01 to 5.00 | 1,787 | 27 | 1,707 | 26 |
| ≥ 5.01 | 1,109 | 17 | 1,162 | 18 |
| Total | 6,570 | 100.0 | 6,544 | 100.0 |
Results are shown in
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, 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 (4 deaths in tamoxifen group vs. 5 deaths in placebo group).
Although there was a non-significant reduction in the number of hip fractures (9 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
For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing 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
| TYPE OF EVENT | # OF EVENTS | RATE/1,000 WOMEN/YEAR | 95% CI | |||
|---|---|---|---|---|---|---|
| PLACEBO | TAMOXIFEN | PLACEBO | TAMOXIFEN | RR | LIMITS | |
| Invasive Breast Cancer | 156 | 86 | 6.49 | 3.58 | 0.56 | 0.43 to 0.72 |
| Age ≤ 49 | 59 | 38 | 6.34 | 4.11 | 0.65 | 0.43 to 0.98 |
| Age 50 to 59 | 46 | 25 | 6.31 | 3.53 | 0.56 | 0.35 to 0.91 |
| Age ≥ 60 | 51 | 23 | 7.17 | 3.22 | 0.45 | 0.27 to 0.74 |
| Risk Factors for Breast Cancer History, LCIS | ||||||
| No | 140 | 78 | 6.23 | 3.51 | 0.56 | 0.43 to 0.74 |
| Yes | 16 | 8 | 12.73 | 6.33 | 0.50 | 0.21 to 1.17 |
| History, Atypical Hyperplasia | ||||||
| No | 138 | 84 | 6.37 | 3.89 | 0.61 | 0.47 to 0.80 |
| Yes | 18 | 2 | 8.69 | 1.05 | 0.12 | 0.03 to 0.52 |
| No. First Degree Relatives | ||||||
| 0 | 32 | 17 | 5.97 | 3.26 | 0.55 | 0.30 to 0.98 |
| 1 | 80 | 45 | 5.81 | 3.31 | 0.57 | 0.40 to 0.82 |
| 2 | 35 | 18 | 8.92 | 4.67 | 0.52 | 0.30 to 0.92 |
| ≥ 3 | 9 | 6 | 13.33 | 7.58 | 0.57 | 0.20 to 1.59 |
| 5 Year Predicted Breast Cancer Risk (as calculated by the Gail Model) | ||||||
| ≤ 2.00% | 31 | 13 | 5.36 | 2.26 | 0.42 | 0.22 to 0.81 |
| 2.01 to 3.00% | 39 | 28 | 5.25 | 3.83 | 0.73 | 0.45 to 1.18 |
| 3.01 to 5.00% | 36 | 26 | 5.37 | 4.06 | 0.76 | 0.46 to 1.26 |
| ≥ 5.00% | 50 | 19 | 13.15 | 4.71 | 0.36 | 0.21 to 0.61 |
| DCIS | 35 | 23 | 1.47 | 0.97 | 0.66 | 0.39 to 1.11 |
| Fractures (protocol-specified sites) | 92Two women had hip and wrist fractures | 76 | 3.87 | 3.20 | 0.61 | 0.83 to 1.12 |
| Hip | 20 | 9 | 0.84 | 0.38 | 0.45 | 0.18 to 1.04 |
| WristIncludes Colles' and other lower radius fractures | 74 | 69 | 3.11 | 2.91 | 0.93 | 0.67 to 1.29 |
| Total Ischemic Events | 59 | 61 | 2.47 | 2.57 | 1.04 | 0.71 to 1.51 |
| Myocardial Infarction | 27 | 27 | 1.13 | 1.13 | 1.00 | 0.57 to 1.78 |
| Fatal | 8 | 7 | 0.33 | 0.29 | 0.88 | 0.27 to 2.77 |
| Nonfatal | 19 | 20 | 0.79 | 0.84 | 1.06 | 0.54 to 2.09 |
| AnginaRequiring angioplasty or CABG | 12 | 12 | 0.50 | 0.50 | 1.00 | 0.41 to 2.44 |
| Acute Ischemic SyndromeNew Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization without surgery | 20 | 22 | 0.84 | 0.92 | 1.11 | 0.58 to 2.13 |
| Uterine Malignancies (among women with an intact uterus)Updated long-term follow-up data (median 6.9 years) from NSABP P-1 study added after cut-off for the other information in this table. | 17 | 57 | ||||
| Endometrial Adenocarcinoma | 17 | 53 | 0.71 | 2.20 | ||
| Uterine Sarcoma | 0 | 4 | 0.0 | 0.17 | ||
| StrokeSeven cases were fatal; three in the placebo group and four in the tamoxifen group | 24 | 34 | 1.00 | 1.43 | 1.42 | 0.82 to 2.51 |
| Transient Ischemic Attack | 21 | 18 | 0.88 | 0.75 | 0.86 | 0.43 to 1.70 |
| Pulmonary EmboliThree cases in the tamoxifen group were fatal | 6 | 18 | 0.25 | 0.75 | 3.01 | 1.15 to 9.27 |
| Deep-Vein ThrombosisAll but three cases in each group required hospitalization | 19 | 30 | 0.79 | 1.26 | 1.59 | 0.86 to 2.98 |
| Cataracts Developing on StudyBased on women without cataracts at baseline (6,230 Placebo, 6,199 Tamoxifen) | 483 | 540 | 22.51 | 25.41 | 1.13 | 1.00 to 1.28 |
| Underwent Cataract Surgery | 63 | 101 | 2.83 | 4.57 | 1.62 | 1.18 to 2.22 |
| Underwent Cataract SurgeryAll women (6,707 Placebo, 6,681 Tamoxifen) | 129 | 201 | 5.44 | 8.56 | 1.58 | 1.26 to 1.97 |
| Staging Parameter | Placebo | Tamoxifen | Total |
|---|---|---|---|
| N = 156 | N = 86 | N = 242 | |
Tumor size: | |||
| T1 | 117 | 60 | 177 |
| T2 | 28 | 20 | 48 |
| T3 | 7 | 3 | 10 |
| T4 | 1 | 2 | 3 |
| Unknown | 3 | 1 | 4 |
Nodal status: | |||
| Negative | 103 | 56 | 159 |
| 1 to 3 positive nodes | 29 | 14 | 43 |
| ≥ 4 positive nodes | 10 | 12 | 22 |
| Unknown | 14 | 4 | 18 |
Stage: | |||
| I | 88 | 47 | 135 |
| II: node negative | 15 | 9 | 24 |
| II: node positive | 33 | 22 | 55 |
| III | 6 | 4 | 10 |
| IV | 2One participant presented with a suspicious bone scan but did not have documented metastases. She subsequently died of metastatic breast cancer. | 1 | 3 |
| Unknown | 12 | 3 | 15 |
Estrogen receptor: | |||
| Positive | 115 | 38 | 153 |
| Negative | 27 | 36 | 63 |
| Unknown | 14 | 12 | 26 |
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, 5,408 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 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.
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
Tamoxifen citrate tablets are contraindicated in patients with known hypersensitivity to the drug or any of its ingredients.
Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients.
Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen as compared to placebo.
When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (see
Tamoxifen citrate tablets are contraindicated in patients with known hypersensitivity to the drug or any of its ingredients.
Tamoxifen citrate tablets are contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep-vein thrombosis or pulmonary embolus.
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen.
Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect.
One patient receiving tamoxifen with concomitant phenobarbital exhibited a steady-state serum level of tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen.
Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, tamoxifen should not be administered with anastrozole (see
Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmaxby 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
In the anastrozole adjuvant trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see