Four prospective studies evaluating tamoxifen for reducing the risk of invasive breast cancer have been published: the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT, P-1),36,37 the Royal Marsden Hospital Tamoxifen Chemoprevention Trial,38-40 the Italian Tamoxifen Prevention Study,41-43 and the International Breast Intervention Study I (IBIS-I).44,45 See Tables 10-1 and 10-2.
Breast Cancer Prevention Trial (BCPT, P-1)
The National Cancer Institute in collaboration with NSABP launched the BCPT P-1,36 a randomized, placebo-controlled, double-blind clinical trial in 1992. The primary aim of the trial was to evaluate the effectiveness of 20 mg/day of tamoxifen (versus placebo) taken orally for 5 years for the prevention of invasive breast cancer in high-risk women. Secondary aims of the trial assessed osteoporotic fractures and cardiovascular disease in women on tamoxifen compared to the control group.
Eligible participants were 60 years or older, or 35 to 59 years of age with a 5-year predicted risk of breast cancer of at least 1.66% as indicated by the Gail model, or had a history of lobular carcinoma in situ (LCIS). The trial was terminated after a median follow-up time was 54.6 months when an interim analysis showed that statistical significance was achieved in a number of study end points. This decrease was only evident in estrogen receptor-positive breast cancers, with no significant change seen in estrogen receptor-negative tumors. The median follow-up time at the end point was 48 months, at which time a 49% (p < 0.00001) decreased risk of invasive breast cancer in the total study population was documented, with the greatest benefit seen in women of ages 60 and older. Overall, a total of 264 invasive cases were documented; 175 cases occurred in the placebo group, compared with 89 cases in the tamoxifen group (risk ratio, 0.51; 95% confidence interval [CI], 0.39–0.66; p < 0.00001). There was a 50% reduction in the rate of noninvasive breast cancer in women taking tamoxifen. The relative risks (RR) for invasive breast cancer reduction were 0.56 for women less than 50 years of age; 0.49 for women 50 to 59 years of age; and 0.45 for women 60 years of age and older.
After 7 years of follow-up in BCPT,46 the cumulative rate of invasive breast cancer was reduced 43% in the tamoxifen group and the cumulative rate of noninvasive breast cancer was reduced 37%. The BCPT revealed that substantial net benefit accrues for women with a diagnosis of either LCIS or atypical hyperplasia who take tamoxifen. Among women with a history of LCIS, the reduction in risk was 46% (RR, 0.54; 95% CI, 0.27–1.02). Among women with a history of atypical hyperplasia, the reduction in risk was 75%; tamoxifen continued to reduce the occurrence of ER-positive tumors by 62%, but no difference was seen in the occurrence of ER-negative tumors.
Secondary outcomes in the BCPT included osteoporotic fractures and cardiovascular events. Tamoxifen is known to have estrogen agonist–like effects on both mineral density and serum cholesterol levels in postmenopausal women.47,48 Women in the tamoxifen group had a 32% reduction in hip, spine, and distal radius fractures. Most fractures (89%) occurred in women aged 50 years or older and tamoxifen reduced fractures in this group by 29%.
Adverse outcomes related to tamoxifen were significantly higher in women over the age of 50 when compared to their younger counterparts. Women on tamoxifen were found to have twice the incidence of pulmonary embolism compared to those on placebo. While incidences of deep vein thrombosis, stoke, and transient ischemic attack were not statistically significant, there was a higher incidence in women on tamoxifen, and thus the concern lies for development of these events in women on tamoxifen.
Women in the tamoxifen arm of the trial were found to have a 3.3 times greater risk of developing invasive endometrial carcinoma than women in the placebo arm. Of the 70 cases of endometrial cancer (17 in the placebo group and 53 in the tamoxifen froup) 67 cases were International Federation of Gynecology and Obstetrics (FIGO) stages 0 or 1 and thus had excellent clinical prognoses with treatment.
An increase of 21% in the development of cataracts was seen in women who were free of cataracts at initiation of the trial. The number of cataract surgeries was also increased by 39% in women taking tamoxifen. Vasomotor symptoms, mainly hot flashes, were reported by 46% of women on tamoxifen and only 29% of women in the placebo arm; whereas an increase in vaginal discharge was reported in 29% of women taking tamoxifen and 13% of women taking placebo. Tamoxifen was not associated with an increased risk of developing depressive symptoms comparing the tamoxifen and placebo groups in the BCPT.49,50
Royal Marsden Hospital (RMH) Tamoxifen Chemoprevention Trial
RMH Tamoxifen Chemoprevention Trial was a randomized, placebo-controlled clinical trial initiated in 1986 and the aim of this trial was to assess whether tamoxifen (20 mg/day for up to 8 years) would prevent breast cancer in healthy women at increased risk of breast cancer based on family history.38-40 Eligible women were ages 30 years to 70 years with least one first-degree relative younger than 50 years with breast cancer, one first-degree relative with bilateral breast cancer, or one affected first-degree relative of any age and another affected first- or second-degree relative. Women were allowed to use HRT during the trial. In initial reports, a total of 70 invasive and noninvasive breast cancers occurred among the women in this trial, and the frequency of breast cancer was the same for women receiving tamoxifen or placebo.38,51 After a median follow-up 13 years, the trial reported a statistically significant decrease in ER-positive tumors.52
Italian Tamoxifen Prevention Trial
The Italian Tamoxifen Prevention Trial was a randomized, placebo-controlled, double-blind clinical trial, initiated to evaluate the effectiveness of tamoxifen in preventing breast cancer.41 The primary aim of this trial was to evaluate the effectiveness of 20 mg/day of tamoxifen orally for 5 years in preventing the occurrence of breast cancer versus placebo in healthy women, with the primary end points being reduction in the incidence of, and mortality from, breast cancer. Because of the potential side effect of endometrial cancer, the study was restricted to women between the ages of 35 and 70 and who had undergone a hysterectomy. More than 5400 women were randomized into either the tamoxifen 20 mg/day or the placebo group. The trial was ended prematurely because of a 26.3% dropout rate for women already randomized.
In a subgroup analysis,41 women are at increased risk for ER-positive breast cancer. This group included women taller than 160 cm (the median height of the group), with at least one functioning ovary, who had menarche when they were no older than 13 years, and who had no full-term pregnancy before 24 years of age. This group of 702 women (13% of the trial population) was classified as high risk. Tamoxifen reduced the incidence of breast cancer in the high-risk group, but it had no effect in the low-risk group.
After 11 years of follow-up, in the group defined as "high risk" with at least one functioning ovary, there was a 77% reduction in the incidence of breast cancer.42 This trial demonstrated that appropriate selection of women at high-risk for developing hormone receptor-positive breast cancer led to benefit from tamoxifen intervention. The update after 11 years of follow-up also confirmed the finding that tamoxifen in addition to estrogen replacement therapy is protective against breast cancer development, although this approach is not used in North America.
International Breast Cancer Intervention Study I (IBIS-I)
The IBIS-I trial was a randomized, placebo-controlled study, with design and outcomes similar to that of BCPT, initiated in 1992 to evaluate whether tamoxifen reduced the risk of invasive breast cancer in women at increased risk.44 The primary aim of the trial was to evaluate the effectiveness of 20 mg/day of tamoxifen (versus placebo) orally for 5 years in preventing the occurrence of both invasive and in situ breast cancer in women deemed at high risk. Selection criteria for the trial's high-risk patients required that women aged 45 to 70 have at least a 2-fold RR, women aged 40 to 44 needed at least a 4-fold RR, and women aged 35 to 39 years of age had at least a 10-fold RR of developing breast cancer.53 Risk factors involved in determining the RR of breast cancer development included family history, history of LCIS, history of atypical hyperplasia, benign breast biopsies, and nulliparity, and the primary end point was the incidence of breast cancer including ductal carcinoma in situ (DCIS).
During 9 years of recruitment, more than 7000 women were enrolled in the trial, approximately 60% had 2 or more first-degree relatives with breast cancer, and 60% of the study cohort had a 10-year risk of developing breast cancer of between 5% and 10%. One-third of women had hysterectomies previously. HRT use was permitted during the trial, and approximately 40% of women used HRT at some point during this trial. The primary end point was the incidence of breast cancer including DCIS.
After a median follow up of 50 months, 170 cases of breast cancers, including DCIS, had been diagnosed, with 32% fewer cases among the women taking tamoxifen. This risk reduction result was virtually identical to that found in the BCPT among women who did not have atypical hyperplasia. As with the BCPT, that risk reduction was only seen with estrogen receptor-positive tumors and not with estrogen receptor-negative tumors. Of women in the trial who concomitantly used HRT with tamoxifen, there was no benefit form tamoxifen. While there was no reduction in the incidence of breast cancer in women concomitantly using HRT and tamoxifen, a risk reduction was seen among women who had a history of prior HRT use and were assigned to tamoxifen in the trial: these women experienced a 57% risk reduction in their risk for breast cancer.
Additional analysis with a median follow-up of 96 months after randomization in IBIS-I revealed a continuing 27% reduction in the risk of breast cancer among the women taking tamoxifen.45 The risk-reducing effect of tamoxifen was fairly constant for the entire follow-up period, and no lessening of benefit was observed for up to 10 years after randomization. Among women who never used HRT or who used it only before the trial, there was a statistically significant 51% reduction in ER-positive breast cancers in the tamoxifen group compared with the placebo group. For women who used HRT during any point of the trial, no clear benefit of tamoxifen was seen in reducing the risk of breast cancer. Results were similar regardless of the HRT preparations used (ie, either estrogen only or combined estrogen and progestin). HRT use was not associated with the development of ER-negative breast cancers, either during the active treatment period or during subsequent follow-up. The risk reduction observed may be smaller that that seen in the NSABP BCPT, both because patients enrolled onto IBIS-I were allowed to take HRT during the trial and because few women in IBIS-I had atypical hyperplasia where a large reduction in incidence of invasive breast cancer was seen in BCPT.
The overall risk of clotting events was increased in tamoxifen users, with a 2-fold increase in risk of venous thromboembolism. As with the BCPT, this risk was seen predominately in women over the age of 50 years and in those women with a recent history of surgery. The excess of thromboembolic events was found only in the active treatment phase. Though the risk was not significant, there was an increase in risk of endometrial cancer in women taking tamoxifen, especially among women aged 50 years or older. As observed in the BCPT, the majority cases of endometrial cancer diagnosed were FIGO stages 0 or 1.
Summary of the Tamoxifen Chemoprevention Trials
Data from all 4 trials combined concluded that tamoxifen decreased breast cancer incidence by 38% (p < 0.0001).54 The risk reduction for development of estrogen receptor-positive breast cancers was 48% (RR, 0.52; 95% CI, 36-58; p < 0.0001). No significant risk reduction was seen in the incidence of estrogen receptor-negative breast cancers. Venous thromboembolic events were found to be nearly doubled in women using tamoxifen in all trials, with reduction in this risk seen with concomitant use of low-dose aspirin. Rates of endometrial cancer were also found to be increased in all trials in women using tamoxifen, with a reduction in this risk seen by excluding women at increased risk of endometrial cancer, and higher risks in women of the age of 50 years. Overall, there was no effect on mortality from all causes; however, these trials were not powered or designed to analyze all-cause mortality events.