Thirty years ago, tamoxifen was shown to prevent the induction and promotion of carcinogen-induced mammary cancer in rats.92,200 Similarly, tamoxifen was also shown to prevent the development of mammary cancer induced by ionizing radiation in rats. These laboratory observations, coupled with the emerging preliminary clinical observation that adjuvant tamoxifen could prevent contralateral breast cancer in women,201 provided a rationale for Powles to start a toxicology study at the Royal Marsden Hospital, London, UK to test whether tamoxifen would be acceptable to prevent breast cancer in high-risk women. This vanguard study opened for recruitment in 19 8 6202 and was to provide important toxicological and compliance data for subsequent trialists.
This toxicology and compliance study was supplemented by parallel investigations of tamoxifen as a chemopreventive in animal models of tumorigenesis122 and the safety studies of tamoxifen to establish the effects on bone and circulating lipids (see Section 8.08.9).
In the decade following the Powles initiative, several studies were started to answer the question: ''Does tamoxifen have worth in the prevention of breast cancer in select high-risk women?'' Eventually four studies were available to evaluate the veracity of the question - the Royal Marsden study, the NSABP/NCI study, the Italian study, and the International Breast Intervention Study (IBIS). The results have been adequately summarized by Cuzick and coworkers203 but the NSABP Study will be presented in detail because it was the only prospective study to achieve its recruitment goal.
The NSABP P-1 study opened in the USA and Canada in May of 1992 with an accrual goal of 16 000 high-risk women to be screened and recruited at 100 North American sites. It closed after accruing 13 338 in 1997 due to the high-risk status of the participants. Those eligible for entry included any woman over the age of 60 or women between the ages of 35 and 59 whose 5-year risk of developing breast cancer, as predicted by the Gail model,204 was equal to that of a 60-year-old woman. Additionally, any woman over age 35 with a diagnosis of lobular carcinoma in situ (LCIS) treated by biopsy alone was eligible for entry to the study. In the absence of LCIS, the risk factors necessary to enter the study varied with age, such that a 35-year-old woman must have a relative risk (RR) of 5.07, whereas the required RR for a 45-year-old woman was 1.79. Routine endometrial biopsies to evaluate the incidence of endometrial carcinoma in both arms of the study were also performed.
The breast cancer risk of women enrolled in the study was extremely high with no age group having an RR of less than 4, including the over-60s group. Recruitment was also balanced with about one-third younger than 50 years, one-third between 50 and 60 years old, and one-third older than 60 years. Secondary end points of the study included the effect of tamoxifen on the incidence of fractures and cardiovascular deaths. Most importantly, the study planned to provide the first information about the role of genetic markers in the etiology of breast cancer. Unfortunately the question of whether tamoxifen has a role to play in the treatment of women who are found to carry somatic mutations in the BRCA-1 and BRCA-2 gene could not adequately be answered205 because of the low incidence of women with mutations in the P-1 study overall.
The first results of the NSABP study were reported in September 1998, after a mean follow-up of 47.7 months.206 There were a total of 368 invasive and noninvasive breast cancers in the participants; 124 in the tamoxifen group and 224 in the placebo group. A 49% reduction in the risk of invasive breast cancer was seen in the tamoxifen group and a 50% reduction in the risk of noninvasive breast cancer was observed. A subset analysis of women at risk due to a diagnosis of LCIS demonstrated a 56% reduction in this group. The most dramatic reduction was seen in women at risk due to atypical hyperplasia where risk was reduced by 86%.
The benefits of tamoxifen were observed in all age groups with a relative risk of breast cancer ranging from 0.45 in women aged 60 and older to 0.49 for those in the 50-59-year age group and 0.56 for women aged 49 and younger. A benefit for tamoxifen was also observed for women with all levels of breast cancer risk within the study, indicating that the benefits of tamoxifen are not confined to a particular lower risk or higher risk subset. Benefits were observed in women at risk on the basis of family history and those whose risk was due to other factors.
As expected, the effect of tamoxifen occurred on the incidence of estrogen receptor-positive tumors which were reduced by 69% per year. The rate of estrogen receptor-negative tumors in the tamoxifen group (1.46 per 1000 women) did not significantly differ from the placebo group (1.20 per 1000 women). Tamoxifen reduced the rate of invasive cancers of all sizes but the greatest difference between the groups was the incidence of tumors 2.0 cm or less. Tamoxifen also reduced the incidence of both node-positive and node-negative breast cancer. The beneficial effects of tamoxifen were observed for each year of follow-up in the study. After year 1 the risk was reduced by 33% and in year 5 by 69%.
Tamoxifen also reduced the incidence of osteoporotic fractures of the hip, spine, and radius by 19%. However, the difference approached, but did not reach, statistical significance. This reduction was greatest in women aged 50 and older at study entry. No difference in the risk of myocardial infarction, angina, coronary artery bypass grafting, or angioplasty was noted between the groups.
This study confirmed the association between tamoxifen and endometrial carcinoma. The relative risk of endometrial cancer in the tamoxifen group was 2.5. The increased risk was seen in women aged 50 and older whose relative risk was 4.01. All endometrial cancers in the tamoxifen group were grade 1 and none of the women on the tamoxifen died of endometrial cancer. There was one endometrial cancer death in the placebo group. Although there is no doubt that tamoxifen increases the risk of endometrial cancer, it is important to recognize that this increase translates to an incidence of 2.3 women per 1000 per year who develop endometrial carcinoma.
More women in the tamoxifen group developed deep vein thrombosis (DVT) than in the placebo group. Again, this excess risk was confined to women aged 50 and older. The relative risk of DVT in the older age group was 1.71 (95% CI 0.85 to 3.58). An increase in pulmonary emboli was also seen in the older women taking tamoxifen, with a relative risk of approximately 3. Three deaths from pulmonary emboli occurred in the tamoxifen arm, but all were in women with significant comorbidities. An increased incidence of stroke (RR 1.75) was also seen in the tamoxifen group, but this did not reach statistical significance.
An assessment of the incidence of cataract formation was made using patient self-report. A small increase in cataracts was noted in the tamoxifen group: a rate of 24.8 women per 1000 compared to 21.7 in the placebo group. There was also an increased risk of cataract surgery in the women on tamoxifen. These differences were marginally statistically significant and observed in the older patients in the study. These findings emphasize the need to assess the patient's overall health status before making a decision to use tamoxifen for breast cancer risk reduction. These observations are also particularly interesting based on the early controversy in the 1960s (see Section 8.08.2) about the safety of this drug group.
An assessment of quality of life showed no difference in depression scores between groups. Hot flushes were noted in 81% of the women on tamoxifen compared to 69% of the placebo group and the tamoxifen-associated hot flushes appeared to be of greater severity than those in the placebo group. Moderately bothersome or severe vaginal discharge was reported by 29% of the women in tamoxifen group and 13% in the placebo group. No differences in occurrence of irregular menses, nausea, fluid retention, skin changes, or weight gain or loss were reported.207'208
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