Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent the progression of premalignant lesions to invasive carcinoma.[1,2] Tamoxifen(Drug information on tamoxifen) is classified as a first-generation selective estrogen-receptor modulator (SERM). It is a proven treatment for breast cancer, which has encouraged its testing as a chemopreventive agent in healthy women.[3] Four randomized prospective clinical trials have used tamoxifen as a chemopreventive agent for breast cancer. Two of the trials-the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study and the International Breast Cancer Intervention Study (IBIS-I)-did demonstrate a reduction in breast cancer risk with tamoxifen. The Royal Marsden Hospital Chemoprevention Trial, a pilot study for the IBIS-I trial, and the initial analysis of the Italian Tamoxifen Prevention Study revealed no decrease in the incidence of breast cancer among women using tamoxifen. Raloxifene(Drug information on raloxifene) (Evista) is a secondgeneration SERM that prevents loss of bone mineral density. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was originally designed to determine whether raloxifene reduced the risk of fracture in postmenopausal women with osteoporosis, with the incidence of breast cancer as a secondary end point. In this article, we review data from each of these five studies and discuss the differences among the trials (Table 1). Breast Cancer Prevention Trial In 1992, the National Cancer Institute in collaboration with the NSABP launched the Breast Cancer Prevention Trial (BCPT, P-1).[4] The primary aim of this double-blind, placebo-controlled, randomized clinical trial was to determine whether tamoxifen administered for 5 years prevented invasive breast cancer in women at increased risk. Eligible women were age 60 or older, were age 35 to 59 with a 5-year predicted risk of breast cancer of at least 1.66%, or had a history of lobular carcinoma in situ (LCIS). Risk was estimated using the Gail model,[5] which considers current age, age at menarche, age at first live birth, number of firstdegree relatives with breast cancer, and the number of breast biopsies ever performed. A previous diagnosis of atypical hyperplasia doubles the estimated risk. Between June 1, 1992, and September 30, 1997, 13,388 women entered the trial and were randomly assigned to receive tamoxifen at 20 mg/d or placebo. Almost all the participants were white (96.4%), more than one-third (37.1%) had had a hysterectomy, and more than one-half (56.8%) had one first-degree relative with breast cancer. The trial was stopped in March 1998, and results were reported, because statistical significance had been achieved in a number of study end points. Trial Results
The median follow-up time was 54.6 months. Through July 1998, a total of 368 invasive and noninvasive breast cancers developed among the 13,175 women with evaluable end points. The overall risk of invasive breast cancer was reduced by 49%. There were 175 cases of invasive breast cancer in the placebo group compared with 89 in the tamoxifen group (risk ratio = 0.51; 95% confidence interval [CI] = 0.39-0.66; P < .00001). The annual rate of invasive breast among women taking tamoxifen was 3.4 per 1,000 women, compared with 6.8 per 1,000 women taking placebo. The risk of invasive breast cancer was reduced in all groups in the trial. For noninvasive breast cancer, risk was reduced by 50%, with 69 cases in women receiving placebo and 35 in those receiving tamoxifen (P < .002). The average annual rate of noninvasive breast cancer per 1,000 women was 2.68 in the placebo group compared with 1.35 in the tamoxifen group. The BCPT showed that tamoxifen confers a substantial net benefit in women with a diagnosis of either LCIS or atypical hyperplasia. For women with a history of LCIS, the reduction in risk was 56% (risk ratio = 0.44; 95% CI = 0.16-1.06), and for women with a history of atypical hyperplasia, risk was reduced by 86% (risk ratio = 0.14; 95% CI = 0.03- 0.47). Tamoxifen reduced the incidence of estrogen-receptor-positive tumors by 69%, but there was no difference in the incidence of estrogenreceptor- negative tumors. The incidence of osteoporotic fractures involving the hip, spine, and radius was reduced by 19% among women taking tamoxifen (111 events vs 137 events in the placebo group), and the 45% reduction in fractures of the hip missed reaching statistical significance because of the small number of events reported. Adverse Effects
Women who received tamoxifen had a 2.53 times greater risk of developing invasive endometrial cancer than did women who received placebo (95% CI = 1.35-4.97). The average annual rate per 1,000 women was 2.30 in the tamoxifen group and 0.91 in the placebo group. The increased risk was seen predominantly among women aged 50 and over (in women 49 or younger, the risk ratio was 1.21 with a 95% CI = 0.41-3.60; in women older than 50, the risk ratio was 4.01 with a 95% CI = 1.70-10.90). All cases of invasive endometrial cancer that occurred among women receiving tamoxifen were classified as stage 0 or I according to the International Federation of Gynecology and Obstetrics (FIGO). The number of thromboembolic events increased among women taking tamoxifen, particularly those aged 50 years and older. The event rate for pulmonary embolism reached statistical significance. The rate of cataract development increased marginally (by 14%) in women taking tamoxifen who were free of cataracts at the time of study entry. The only symptomatic differences between the placebo and tamoxifen group were bothersome hot flashes and vaginal discharge. Bothersome hot flashes were reported by 46% of women in the tamoxifen group compared with 29% in the placebo group. Moderately bothersome or worse vaginal discharge was reported in 29% of women in the tamoxifen group compared with 13% of those in the placebo group. This randomized clinical trial provided the first information to support the hypothesis that breast cancer can be prevented in women at increased risk for the disease. Italian Tamoxifen Prevention Study The Italian Tamoxifen Prevention Study was initiated in October 1992.[6] This double-blind placebocontrolled, randomized trial evaluated tamoxifen in healthy women aged 35 to 70 years. In view of the potential side effect of endometrial cancer, the study was restricted to women who had undergone a hysterectomy. Recruitment for the study started in October 1992 and ended in July 1997. The trialist and data-monitoring committee decided to end recruitment primarily because 26% of women dropped out of this study; 5,408 women were randomized to receive tamoxifen at 20 mg/d or placebo for 5 years. Among the 5,378 women with complete data, 48.3% had a bilateral oophorectomy, and 18.2% had at least one first-degree relative or an aunt with breast cancer. Women were allowed to take hormone replacement therapy (HRT) while participating in the study. The primary end points were reduction in the frequency and mortality of breast cancer. At a median follow-up of 46 months, 41 cases of breast cancer were reported-19 among women in the tamoxifen arm and 22 among women in the placebo arm (P = .6). The number of deaths from vascular disease were lower than expected from the Italian national rates. A subgroup analysis that was not part of the original protocol revealed a protective effect for tamoxifen among women who took HRT during the study period. At the time that the initial results were reported, the conclusion was that tamoxifen did not confer a significant protective effect against breast cancer in women at normal or slightly reduced risk of the disease. Also, women who were using HRT benefited from the administration of tamoxifen. Study Update
An update of the Italian Tamoxifen Prevention Study was reported in 2002.[7] At an extended median follow-up of 81.2 months, 79 cases of breast cancer had been identified. Breast cancer was diagnosed in 45 of 2,708 women receiving placebo and 34 of 2,700 women receiving tamoxifen (odds ratio = 0.76; 95% CI = 0.47-1.60). The difference was not statistically significant (P = .215). Among women who took HRT during the trial, the cumulative frequency of breast cancer was 0.92% (0.17-1.66) in the tamoxifen group and 2.58% (1.30-3.85) in the placebo group. Among women who used HRT either at baseline or during the study, breast cancer was diagnosed in 17 of 791 receiving placebo and 6 of 793 receiving tamoxifen (P = .022). The update supported the trial's original conclusion that tamoxifen provides some benefit in the prevention of breast cancer, but the difference was nonsignificant in women with a normal or slightly reduced risk of the disease. The results also suggest that tamoxifen seems to reduce the risk of breast cancer in women who use HRT compared with nonusers of HRT. Subgroup Analysis
In a subgroup analysis, Veronesi et al[8] were able to identify a group of women at increased risk for estrogen- receptor-positive breast cancer. This group consisted of women taller than 160 cm (the median height of the overall study cohort), with at least one functioning ovary, who had reached menarche no later than age 13, and who had no full-term pregnancy before age 24. This group of 702 (13%) women was classified as high risk. The remaining group of 4,693 (87%) women was classified as low risk. Information on required baseline characteristics was missing for 13 women. In the high-risk group, the risk of breast cancer was increased threefold over that in the low-risk group (hazard ratio = 3.32; 95% CI = 1.78-6.17). Tamoxifen reduced the incidence of breast cancer in the high-risk group (n = 3 vs n = 15 in the placebo group, P = .003); however, it had no effect in the low-risk group (tamoxifen = 31, placebo = 30; P = .89). It is important to emphasize that this subgroup analysis was not used as a stratification factor at the time of randomization. Thus, these findings need to be confirmed in randomized prospective trials.[9] Royal Marsden Hospital Chemoprevention Trial The Royal Marsden Hospital Chemoprevention Trial was initiated in 1986 as a preliminary pilot study for IBIS-I.[10,11] The aim of this randomized, placebo-controlled chemoprevention trial was to assess whether tamoxifen would prevent breast cancer in healthy women at increased risk for the disease based on family history. Each participant had at least one first-degree relative under age 50 with breast cancer, one first-degree relative with bilateral breast cancer, or one affected first-degree relative of any age and another affected firstdegree or second-degree relative. Women were allowed to take HRT during this study. Between October 1986 and April 1996, 2,494 women between the ages of 30 and 70 were randomized to receive tamoxifen at 20 mg/d or placebo for up to 8 years. The primary end point was the occurrence of breast cancer. The median follow-up was 70 months, and 2,471 of the women were analyzed. A total of 70 invasive and noninvasive breast cancers occurred among the women in this trial. The frequency of breast cancer was the same for women receiving tamoxifen or placebo (tamoxifen = 34, placebo = 36; relative risk = 1.06; 95% CI = 0.7-1.7), and there appeared to be no interaction between the use of HRT and the effect of tamoxifen on breast cancer occurrence. A total of 12 cases developed among 523 women who received HRT while on tamoxifen, compared with 13 of 507 women receiving placebo (P = .6). An update of this trial[12,13] reported 75 cases of breast cancer in the placebo group compared with 62 in the tamoxifen group (odds ratio = 0.83; 95% CI = 0.58-1.16). International Breast Cancer Intervention Study Between April 1992 and March 2001, 7,152 women aged 35 to 70 years and at high risk for breast cancer were enrolled in the IBIS-1 trial and randomized to receive tamoxifen at 20 mg/d for 5 years or placebo.[14] Eligible women had risk factors for breast cancer indicating at least a twofold relative risk among those aged 45 to 70 years, a fourfold relative risk among those aged 40 to 44 years, and a 10-fold relative risk among those aged 35 to 39 years. Approximately 60% had two or more first-degree relatives with breast cancer; one-third of women had previously undergone hysterectomies. Use of HRT was permitted, and approximately 40% of women used such therapy at some point during the trial. The primary end point was the incidence of breast cancer, including ductal carcinoma in situ (DCIS). Trial Results
A total of 7,139 women were included in the analysis. At a median follow-up of 50 months, 170 breast cancers had been diagnosed (including DCIS). The rate was 32% (95% CI = 8%-50%) lower in the tamoxifen group than in the placebo group (tamoxifen = 69, placebo = 101; P = .01). The risk of developing estrogen-receptor-positive invasive tumors was reduced by 31%, but there was no reduction in the risk of estrogen-receptor-negative tumors. Among women taking HRT during the trial, 38 cases of breast cancer occurred in the placebo group and 29 in the tamoxifen group (odds ratio = 0.76; 95% CI = 0.47-1.23). Among women who received HRT before the trial only, 21 cases of breast cancer developed in the placebo group and 9 in the tamoxifen group (odds ratio = 0.43; 95% CI = 0.20-0.91). A nonsignificant twofold increase in the incidence of endometrial cancer was found in the tamoxifen group (tamoxifen = 11, placebo = 5; odds ratio = 2.20; 95% CI = 0.80-6.06). The women enrolled in this trial were at moderately increased risk of developing breast cancer, with 60% of the study cohort having a 10-year risk ranging from 5% to 10%. Participation in the trial required at least a twofold relative risk for breast cancer for women aged 45 to 70 years, a fourfold relative risk for women aged 40 to 44 years, and a 10-fold relative risk for women aged 35 to 39 years. Risk factors used included a combination of family history, lobular carcinoma in situ, atypical hyperplasia, nulliparity, and benign breast biopsies. The IBIS-I investigators used a model to predict the absolute 10-year risk of developing breast cancer, but the details of their model have not been published. In contrast, 44% of the women in the NSABP BCPT had greater than a 3% 5-year risk of developing breast cancer, as determined using the validated Gail model.[5] Among women enrolled in the BCPT, tamoxifen reduced the risk of breast cancer by 34% in high-risk women without either atypia or LCIS, which is nearly identical to the 32% reduction in risk seen in the IBIS-I study. Although there was no overall difference in the effect of tamoxifen among women who used HRT compared with those who had never used HRT, tamoxifen did reduce the incidence of breast cancer in women who had used HRT before enrollment in IBIS-I. This reduction is remarkably similar to the findings in the Italian tamoxifen study. In IBIS-I as in the Italian trial, tamoxifen produced a differential effect based on the status of participants' use of HRT. Women who used HRT during the trial achieved a 24% reduction in the risk of invasive breast cancer with tamoxifen use, similar to the 27% reduction observed among women who had never used HRT; women who had used HRT only before initiating tamoxifen therapy (and not during the trial) had a statistically significant 57% reduction in the risk of breast cancer. Adverse Events
All the women in the IBIS-I trial who developed endometrial cancer were postmenopausal at diagnosis. Most of the endometrial cancers occurred in women older than age 50 at the time of randomization. All were FIGO stage I except for one case in the placebo group that was stage II. The rate of thromboembolic events was 2.5 times greater in the tamoxifen group than in the placebo group (95% CI = 1.5-4.4; P = .001), and 42% of these events occurred within 3 months of surgery or after periods of immobility. There were no differences in the number of cerebrovascular accidents, myocardial infarctions, or other vascular events between treatment groups. A significant excess of deaths from all causes occurred in the tamoxifen group (25 vs 11, P = .028). This increase in mortality is of concern, but is not statistically rigorous due to the multiple, unplanned comparisons in the analysis. In summary, IBIS-I confirmed that tamoxifen can reduce the risk of breast cancer in healthy women. Temporary cessation of tamoxifen should be considered during and after major surgeries or periods of immobilization to reduce the risk of thrombosis, according to the investigators.