American Journal of Epidemiology Copyright © 1992 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Vol. 135, No 2 Printed in US. A

Prospects for the Primary Prevention of Breast Cancer

Leslie Bernstein, Ronald K. Ross, and Brian E. Henderson

In this paper, the rationale, stage of development, and known or potential adverse effects of three potential strategies for the prevention of breast cancer are reviewed. Two methods—the use of tamoxifen in postmenopausal women and the use of luteinizing hormone (LH)-releasing hormone agonists in premenopausal women—involve hormonal manipulation. In the premenopausal period, the goal is to reduce the number of ovulatory menstrual cycles a woman experiences in order to reduce her exposure to estrogen and progesterone. Physical activity during adolescence is proposed as a nonhormonal method of accomplishing this. The use of LH-releasing hormone agonists to produce a reversible menopause can also reduce a woman's cumulative exposure to ovarian steroid hormones. Tamoxifen, which is effective in breast cancer therapy, provides endocrine control of estrogen-regulated breast tumor growth. Breast cancer chemoprevention trials using tamoxifen among postmenopausal women have been proposed, and pilot studies are under way. Am J Epidemiol 1992;135:142-52. breast neoplasms; exercise; LH-FSH releasing hormone; primary prevention; tamoxifen

the level of the tumor by competitively inhibiting estradiol binding (4, 5), and it has been labeled an "antiestrogen" on that basis. Tamoxifen also may act as an antitumor agent on the hypothalamic-pituitary axis, where it affects the release of growth hormone, thereby reducing the amount of circulating insulin-like growth factor, a stimulatory growth factor for breast tissue (6). Thus, tamoxifen may provide a model of direct (by interference with estrogen binding to receptors) and indirect (by its effects on the hypothalamic-pituitary axis) endocrine control of estrogen-regulated breast tumor growth. As a result of its efficacy in preventing or delaying breast cancer recurrence, tamoxifen chemoprevention trials in healthy postmenopausal women have been proposed (7, 8) and are being pilot-tested (9). The classic age-specific incidence curve for breast cancer suggests a different hormonal approach for the primary prevention of breast cancer in premenopausal women. The earliest cases of breast cancer occur in late adolescence, several years after menarche. Throughout the reproductive years,

Based on experimental and epidemiologic evidence accumulated over many years (1), there is no longer any doubt that estrogen is a critical factor in breast cancer etiology. Recent findings argue strongly that progesterone, either independently or interactively, also plays an important role (2). In fact, we are now sufficiently knowledgeable about the hormonal etiology of breast cancer that primary prevention, using a variety of approaches to reduce exposure of breast tissue to estrogen and progesterone, is now feasible. Tamoxifen is a synthetic, nonsteroidal antiestrogen in the breast which has proven effective in the treatment of breast cancer (3). Tamoxifen blocks estrogen receptors at Received for publication July 18,1991, and in final form October 2, 1991 Abbreviation: LH, luteinizing hormone From the Department of Preventive Medicine and the Norris Comprehensive Cancer Center, University of Southern California School of Medicine, 1420 San Pablo Street, PMB A-202, Los Angeles, CA 90033. (Reprint requests to Dr. Leslie Bernstein at this address). This work was supported by grants CA 17054 and CA44546 from the National Institutes of Health.

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breast cancer incidence rates increase sharply with age to the time of menopause; after menopause, the rate of increase in incidence slows dramatically to about one sixth of that observed during the premenopausal period. Thus, the age-specific incidence curve is shaped in a major way by the effects of ovarian activity (10). Epidemiologic data on the effects of menarche and menopause on breast cancer risk further support this notion. For each year that menarche is delayed, breast cancer risk is reduced by 5-15 percent (11, 12). Women who experience natural menopause before age 45 years have only one half the breast cancer risk of women whose menopause occurs after age 55 years (13). Artificial menopause, induced by either bilateral oophorectomy or pelvic irradiation, also markedly reduces breast cancer risk, by a slightly greater margin than natural menopause. This series of observations has led to a proposed hormonal intervention strategy: the use of luteinizing hormone (LH)-releasing hormone agonists to induce a reversible menopause at a young age, thereby reducing a woman's cumulative exposure to ovarian steroid hormones, with a concomitant reduction in breast cancer risk (14, 15). A third proposed strategy of primary breast cancer prevention through reduced exposure of the breast to estrogen and progesterone is based on a series of observations of the effect of physical activity during adolescence on menstrual and ovulatory patterns. This strategy has particular appeal because it is not dependent on hormonal manipulation by an exogenous agent. The rationale, stage of development, and known or potential adverse effects of each of these three potential strategies for the prevention of breast cancer are described more fully below. Dietary manipulation is another general strategy for primary breast cancer prevention. Increasing dietary intake of phytoestrogens in soybean products (16, 17), increasing intake of vitamin C (18), and increasing consumption of carotenoids (18-20) have all been proposed to reduce breast cancer risk, but decreasing intake of dietary fat (21)

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has received the most attention. The mechanism by which dietary fat might reduce breast cancer risk has not been fully elucidated. Diet is discussed below only as a possible mediator of exposure to ovarian steroid hormones, particularly during adolescence, through effects on age at onset of menses and frequency of ovulatory menstrual cycles. Dietary intervention as an alternative approach to breast cancer prevention has been fully described and reviewed elsewhere (22) and is not discussed further here. PHYSICAL ACTIVITY

There is substantial evidence that breast cancer risk is directly related to the cumulative number of ovulatory menstrual cycles a woman experiences (23-26). In addition to the effects of age at menarche and age at menopause on breast cancer risk (described above), several other major observations support this hypothesis. There is evidence of international variation in menstrual cycle length that parallels breast cancer risk patterns. For example, low-risk Japanese women tend to have longer regular menstrual cycles than higher-risk US women (25, 27, 28) and would therefore accumulate fewer ovulatory cycles during their reproductive lifetimes. Moreover, women with lifelong histories of irregular menstrual cycle patterns (cycles of very short or very long duration) appear to have a decreased risk of breast cancer (26). Such irregular menstrual cycle patterns may also represent less cumulative exposure to ovarian hormones. Brown (29) has shown that during the adolescent and perimenopausal periods, both short and long cycles have a greater likelihood of being anovulatory. Breast cancer risk is a function not only of age at menarche but also of the length of time it takes to establish a regular pattern of menses (30). Women who start menstruating at an early age and establish regular cycles quickly have a substantially higher risk than women who start menstruating early but have delayed onset of regular cycles. Menstrual cycles near puberty and

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throughout adolescence are more likely to be anovulatory than cycles later in a woman's reproductive life (29, 31-33). Several studies have established that both age at menarche and time since menarche significantly predict the likelihood of ovulatory menstrual cycles, with early menarche associated with more rapid onset of regular ovulatory cycles (23, 34, 35). In their prospective study of Finnish schoolgirls, Apter and Vihko (34) reported that for a girl with menarche before age 12, 80 percent of menstrual cycles are ovulatory within 1-2 years, whereas for a girl with menarche at age 13 or later, it takes 4.5 years for 50 percent of her menstrual cycles to be ovulatory. These effects of early menarche and earlier onset of ovulatory cycles may have longlasting effects on a woman's hormonal patterns as well. Vihko and Apter (24) and Apter et al. (36, 37) have reported that hormonal patterns may be established around the time of puberty. In their prospective study, they demonstrated that, during adolescence, ovulatory cycles in girls who have early menarche (before age 12) are associated with significantly higher levels of estradiol and sex hormone-binding globulin—a protein that binds estradiol and presumably inactivates it—than are such cycles in girls who have later menarche (24, 36). They later showed that this effect of age at menarche on hormonal patterns persisted when these women were assessed in their mid- to late 20s (37). It is important to understand factors which determine onset of menstruation, frequency of ovulation, and menstrual cycle length patterns in the time period soon after menarche and continuing through early reproductive experiences because any such factors could markedly reduce a woman's lifetime risk of breast cancer. Two such factors appear to be physical activity and diet. Premenarcheal girls engaging in strenuous physical activity such as regular ballet training, running, or swimming experience later menarche than girls in the general population (38, 39). A case-control study of factors associated with the onset of menarche conducted in Quebec, Canada, found that girls

who participated in regular competitive physical activities were significantly less likely to have reached menarche early than were nonparticipating girls (40). After the onset of menses, adolescent girls may experience secondary amenorrhea in relation to strenuous physical activity, such that girls engaged in heavy physical training regimens may stop all menstrual activity until their physical activity level declines (38, 39, 4 1 43). It follows that if physical activity alters ovulatory patterns, it may reduce breast cancer risk. There is some evidence to support this contention. A follow-up study by Frisch et al. (44) which compared female college athletes with nonathletes suggested that nonathletes had an 86 percent greater subsequent risk of breast cancer than did athletes. A Finnish study comparing the breast cancer risks of physical education teachers and language teachers showed that physical education teachers had a lower risk of breast cancer than language teachers prior to menopause (45). Among these women, the differences in physical activity levels declined with increasing age. The postmenopausal breast cancer risk of physical education teachers was only slightly lower than that of the language teachers. A study of high school girls was conducted to determine whether moderate physical activity might affect ovulatory frequency and menstrual cycle patterns (35). The menstrual cycles of 168 girls (36 Asians and 132 Caucasians) between the ages of 14 and 17 years were monitored for 6 months. During that time, each girl maintained and returned 2-week menstrual cycle and physical activity calendars, recording each day of menstrual bleeding as well as the number of minutes and type of each physical activity in which she participated in and out of school. Urine samples were collected during two menstrual cycles for each girl in order to determine through the measurement of pregnanediol glucuronide, a progesterone metabolite, whether ovulation had occurred. Major determinants of average cycle length were average weekly energy expenditure (with very active girls having very short cycles with

Primary Prevention of Breast Cancer

presumably short, inadequate luteal phases), age at menarche (with later age associated with long cycles), and race (with Asians having cycles about 2 days longer than those of Caucasians). In this study (35), both age at menarche and years since menarche were significant predictors of whether menstrual cycles were ovulatory, which confirmed the results of earlier studies (23, 34). Taking these two factors into account, girls who, on average, expended more than 600 kilocalories of energy in physical activity per week over the 6-month follow-up period were 2-3 times more likely to have anovulatory menstrual cycles than were girls who participated in little or no physical activity (table 1). Such moderate activity represents sustained participation in 2 or more hours per week of activities like aerobic exercise, swimming, jogging, or tennis. These findings, in conjunction with the observations of Frisch et al. (44) and Apter et al. (45), suggest that participation in sustained levels of moderate physical activity during adolescence could alter breast cancer risk by reducing the frequency of ovulatory menstrual cycles. Given the well-documented additional positive effects of physical activity on cardiovascular health, there is little doubt that such activity should be routinely promoted among adolescent girls. There are well-founded concerns about the reduced bone mineral density in girls who are anovulatory due to extreme physical activity (46), but the impact on bone of more modest physical activity is likely to be minimal. Although less amenable to large-scale population changes than moderate physical activity, diet is another critical factor in determining age at onset of menarche. Under-

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nutrition and anorexia are known to be factors that delay the onset of menses (4749). Well-nourished Western populations have relatively early mean ages at menarche, whereas menarche in females in developing countries occurs considerably later (50). The later menarche of Japanese women compared with US white women is probably due to dietary factors. Japanese women born as late as 1934 had an average age at menarche that was 2 years later than that of US white women born during the same time period (50). Since then, the average age at menarche of Japanese females has gradually declined, but for Japanese women born as late as 1944, the onset of menses was still nearly 1.3 years later than that of US white women. It is less clear whether variations within an adequate and highly varied diet influence age at menarche. A number of investigators have attempted to identify particular components of the diet associated with early onset of menses, with inconsistent results. These include associations between early onset and high energy (51, 52), high fat (53), high protein (54, 55), low carbohydrates (56), and low fiber intake (57). In a series of studies conducted in Quebec, Moisan et al. (40) and Meyer et al. (58) found only weak associations of higher total energy intake with earlier age at menarche. Premenarcheal rhesus monkeys fed highfat diets (31 percent of calories from fat) exhibited earlier onset of menarche and more rapid onset of ovulation after menarche than did monkeys on a control diet (12 percent of calories from fat) (59). Although animals on the high-fat diet did not have accelerated growth, they did have increased levels of estradiol, insulin, and growth hormone.

TABLE 1. The relation between energy expended in physical activities (kcal/week) and the likelihood of anovulation in adolescent girls* Average energy expenditure (kcal/week) S300

301-600

601-930

931-1,400

£1,401

An/Ovf

RRJ

An/Ov

RR

An/Ov

RR

An/Ov

RR

An/Ov

RR

4/26

1.0

3/25

0.9

6/23

2.3

10/18

3.8

7/24

2.3

• Adapted from Bernstein et al. (35). t An/Ov, no. anovulatory/no. ovulatory. $ RR, relative risk of anovulation, adjusted for age at menarche and years since menarche.

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Further study is required to assess the effects of particular dietary patterns on age at menarche and on the frequency of ovulation after menarche within populations in developed countries, where food is readily available. LH-RELEASING HORMONE AGONISTS

Among premenopausal women, another strategy for preventing breast cancer is to substantially reduce the number of ovulatory menstrual cycles by means of medical intervention. Use of combination oral contraceptives effectively accomplishes this. However, combination oral contraceptives apparently do not reduce the risk of breast cancer among premenopausal or perimenopausal women (60), possibly because they compensate for the lack of ovarian hormone production with synthetic estrogen and progesterone in amounts that are at least comparable with those which an ovulating woman would produce. An alternative hormonal approach to inhibiting ovulation that has recently been proposed as a means of preventing breast cancer in premenopausal women is the use of LH-releasing hormone agonists (14, 15), which do not replace ovarian hormones. Experimentally, these drugs cause regression of estrogen-dependent dimethylbenz[a]anthracene-induced rat mammary tumors (61), and clinically, they suppress ovulation and achieve clinical regression of metastatic breast cancer in premenopausal women (6264). As a primary means of preventing breast

cancer, the use of LH-releasing hormone agonists is designed to exploit the preventive aspect of early menopause (14, 15). LHreleasing hormone agonists can totally eliminate ovarian steroid hormone production so as to induce a reversible "bilateral oophorectomy" (65, 66). Such a regimen followed for 5 years during the premenopausal years would lead to a predicted reduction in breast cancer risk of 38 percent, whereas such a regimen followed for 15 years might reduce risk by as much as 80 percent (table 2) (14). Moreover, as with combination oral contraceptives, such a regimen, by preventing ovulation, would markedly reduce ovarian cancer risk as well. The beneficial effect of such ovulation inhibition would, of course, have associated with it some adverse side effects (65, 66). These adverse consequences are those related to a hypoestrogenic state, both acutely and in the long term—in particular, hot flushes, significant bone loss, an increase in low density lipoprotein cholesterol, and probably a significantly increased risk of cardiovascular disease (67, 68). Extensive experience, however, suggests that these harmful side effects can be eliminated by the addition of low-dose estrogen replacement therapy to the regimen. Such a regimen (LHreleasing hormone agonist plus low-dose estrogen replacement therapy) would not affect the protective effect that LH-releasing hormone agonists alone have on ovarian cancer risk, and Pike et al. (14) and Spicer et al. (15) have argued that the replacement estrogen dosage required to eliminate these side effects is sufficiently low to retain the

TABLE 2. Estimated effect of a luteinizing hormone (LH)-releasing hormone agonist, with and without lowdose estrogen replacement therapy, on breast cancer risk* Relative risk Duration of regimen (years)t

5 10 15

LH-releasing hormone agonist only

LH-releasing hormone agonist with low-dose estrogen replacement therapy!

0.62 0.37 0.20

0.68 0.45 0.28

* Predicted risk relative to regularly ovulating women. Adapted from Pike et al. (14). t Calculations were based on the breast tissue aging model of Pike et al. (12). t Given as 0.625 mg of conjugated equine estrogen per day for 21 days of each 28-day cycle.

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major portion of the benefit with regard to breast cancer risk. Intermittent regular addition of a progestogen to the regimen (e.g., medroxyprogesterone acetate for 13 days at a dosage of 10 mg per day, given every fourth 28-day cycle) should avoid any increased risk of endometrial hyperplasia (or carcinoma) associated with low-dose estrogen replacement therapy. Furthermore, this regimen operates as a highly effective hormonal contraceptive method. In addition to the advantages with respect to breast cancer risk, such a regimen may have other notable advantages over low-dose oral contraceptives in terms of long-term health effects. In particular, although data are sparse, LH-releasing hormone agonists combined with low-dose estrogen replacement therapy and intermittent administration of progestogen appear to create a favorable lipid profile, particularly with regard to high density lipoprotein cholesterol levels, and would thus be expected to have a favorable influence on cardiovascular disease risk (14, 15). Moreover, this regimen would probably have no adverse effects on bone mineral content because of the established effects of low-dose estrogen replacement therapy in maintaining bone mass in postmenopausal women. In addition to a need for more studies of biochemical changes and possible health effects of this proposed therapy, technical details must be addressed before a full-scale trial can be implemented. These include but are not limited to 1) the identification of an appropriate target population (the group that has been most widely promoted is women at high risk of breast cancer because of a positive family history) and 2) the required sample size and length of follow-up. In addition, an acceptable mode of delivery for the LH-releasing hormone agonist must be developed, since currently the only available method of administration is monthly injection. TAMOXIFEN

The first proposal for the hormonal chemoprevention of breast cancer was intro-

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duced by Cuzick et al. (7) in 1986. The goal was to treat healthy postmenopausal women at high risk of breast cancer using the "antiestrogenic" drug tamoxifen. The rationale for this proposal was based, in part, on the extensive evidence that the amount of estrogen available to breast tissue is a critical factor in the etiology of human breast cancer. Two years later, a summary analysis of 28 ongoing US, Canadian, and European randomized clinical trials showed a significant reduction in the breast cancer mortality of women over age 50 who were treated with tamoxifen (69). This beneficial effect appears regardless of whether women are lymph node-positive or lymph nodenegative at diagnosis, and regardless of the initial estrogen receptor status of the tumor. The most compelling argument for extending the use of tamoxifen to healthy women at high risk of breast cancer, however, is the lower risk of contralateral primary breast cancer observed among women receiving adjuvant tamoxifen therapy for breast cancer. Spicer et al. (70) have summarized these data in tamoxifen-treated patients versus control patients from five randomized trials (71-75) (table 3), which, overall, show a 38 percent reduction in risk of contralateral breast cancer with tamoxifen treatment. Spicer et al. argue that this effect might have been even greater if tamoxifen TABLE 3. Effect of tamoxifen treatment on the risk of primary contralateral breast cancer in women with postmenopausal breast cancer: results from five randomized controlled clinical trials*

Author(s) and year

Rate of contralateral breast cancer per 100 women followed per year Tamoxifen group

NATOt (71), 1988 0.43 (564)$ Ribeiro and Swindell (72), 1988 0.34(282) Fisher et al. (73), 1989 0.51(1,318) Fornander et al. (74), 1989 >0.43(931) Stewart and Knight (75), 1989 0.27(282)

Control group

0.38 (567) 0.37(306) 1.18(1,326) X).78(915) 0.38(531)

• Adapted from Spicer et al. (70). t NATO, Nolvadex and Adjuvant Trial Organization. $ Numbers in parentheses, no. of patients randomized.

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had been used continuously for extended periods of time in these trials. An ongoing concern which has guarded the optimism about the probable efficacy of such a regimen in primary breast cancer prevention is the possibly adverse antiestrogenic effect of tamoxifen on other organ systems (76). However, tamoxifen shows highly selective antiestrogenic properties and, in fact, appears to be an estrogen agonist in most other tissues (76). Of particular concern has been the possible antiestrogenic effect of tamoxifen on lipid and bone metabolism. There is strong evidence that menopause is associated with a substantial increase in heart disease risk and that this effect is probably due to the loss of ovarian estrogen production (77). Low-dose, orally administered estrogen replacement therapy is associated with a substantial reduction in heart disease (78, 79) and stroke mortality (80). These effects are probably mediated, in part, by the favorable effect of estrogen replacement on lipid profiles; estrogen replacement therapy substantially increases high density lipoprotein cholesterol levels and substantially reduces low density lipoprotein cholesterol levels. Importantly, tamoxifen has no apparent adverse effects on lipids; in fact, tamoxifen appears to create a somewhat favorable lipid profile (70). The most authoritative paper on this topic to date was published by Love et al. (81). As part of a 2-year randomized double-blind, placebo-controlled toxicity trial of tamoxifen in 140 postmenopausal women with a history of node-negative breast cancer (70 of whom were treated with tamoxifen), these investigators found that low density lipoprotein cholesterol levels delined approximately 18 percent and that this decline persisted for at least 1 year of treatment. High density lipoprotein cholesterol levels remained unchanged for the first 6 months of therapy, but compared with baseline values, they were significantly reduced by 7 percent at 1 year. Total cholesterol was also significantly reduced in the tamoxifen-treated group. Overall, because of the large declines in low density lipoprotein cholesterol, the relative amount of high den-

sity lipoprotein cholesterol (i.e., the high density lipoprotein cholesterolrtotal cholesterol ratio) increased among women treated with tamoxifen. Other, smaller studies have reported comparable results (82-85). Nonetheless, since the pattern of lipid changes with tamoxifen is different from that induced by estrogen replacement therapy, since other mechanisms may be involved in the cardioprotective effect of estrogen replacement therapy, and since there are few data on women regarding the potential benefits of reducing low density lipoprotein cholesterol with regard to cardiovascular disease risk, the effect of long-term tamoxifen use in this regard remains uncertain. The Scottish Adjuvant Tamoxifen Trial provides some preliminary evidence that tamoxifen may have a beneficial effect on coronary heart disease risk (86, 87). In this randomized trial, a group of women have received 20 mg of tamoxifen per day for at least 5 years, with follow-up ranging from 5 to 11 years. Among postmenopausal women, those treated with tamoxifen have a statistically significant reduction in death due to acute myocardial infarction compared with control patients, although detailed results have yet to be published. Available evidence on the effects of tamoxifen on bone mineral density are also encouraging. Two studies evaluating this issue have reported slight increases in the density of the lumbar spine during tamoxifen treatment for postmenopausal breast cancer (88, 89). Although rates of osteoporotic fracture following tamoxifen use have not been studied, these data suggest that, as with estrogen replacement therapy, fracture risk may be reduced. There are other lingering issues which suggest caution in the initiation of a full-scale trial. There are reports that tamoxifen is associated with a substantially elevated risk of endometrial cancer of a magnitude comparable with that related to estrogen replacement therapy (74, 90-94). Although not every tamoxifen trial has reported such an effect (75), both experimental evidence and the biochemical effects of tamoxifen treatment support a causal relation. Tamoxifen

Primary Prevention of Breast Cancer

acts directly on the ovaries to stimulate estrogen biosynthesis, and in premenopausal women, an increase in plasma estrogen levels after tamoxifen treatment has been shown (95). Tamoxifen has been used to improve luteal function (96) and to induce ovulation (97). It has also been shown to cause estrogen-like changes in the vaginal epithelium (98) and endometrium (99) of some women. In nude mice given transplants of human endometrial cancer, tamoxifen increases the growth rate of estrogen receptor-positive tumors (100). Gottardis et al. (101) have reported that while tamoxifen inhibits the growth of breast tumors implanted in athymic mice, it stimulates the growth of implanted endometrial tumors. In rats, although low doses of tamoxifen inhibit estrogen-stimulated rises in uterine wet weight and vaginal cornification, high doses produce increases in uterine weight that are about 50 percent as great as those produced by estradiol administration (102). Finally, Anzai et al. (103) have demonstrated that tamoxifen stimulates the division of endometrial cancer cells in culture. Another concern is that tamoxifen may have estrogen-like effects on the liver. In rats, estrogens act as promoters of liver carcinogenesis (104). Jordan (76) reports that in large doses or with extended exposure, tamoxifen has produced rat liver tumors. To date, however, no increase in liver tumor incidence has been observed among tamoxifen-treated patients, although Fornander et al. (74) reported two cases of hepatocellular carcinoma among their patients receiving tamoxifen. A possibly increased risk of thromboembolic disease associated with tamoxifen has been suggested (105, 106) but has not been well documented to date. Among postmenopausal women receiving long-term adjuvant tamoxifen therapy, small decreases in the levels of antithrombin III have been reported (83, 107), although these values are generally within the normal range. Thus, a history of blood clotting disorders may be a contraindication to tamoxifen treatment. Although tamoxifen probably reduces certain acute menopausal effects such as vagi-

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nal dryness, the drug clearly has no beneficial effect on hot flushes (there are data which suggest that the opposite may be true (108)), and the relation between tamoxifen and other acute symptoms of menopause is largely unstudied. In summary, based on existing evidence, concerns regarding bone and lipids appear to be largely unfounded. Endometrial cancer, thromboembolic disease, and hot flushes continue to be legitimate concerns. However, tamoxifen has few other acute side effects, which increases the likelihood of long-term compliance in large-scale trials. In addition to resolving the lingering questions regarding short- and long-term health effects of tamoxifen, many technical issues must be addressed before a breast cancer prevention trial can be initiated. These include but are not limited to 1) the identification of an appropriate target population (a recent proposal suggests including nulliparous women with particular types of highrisk mammographic parenchymal patterns, women with a family history of breast cancer, and women who have had a benign lesion with proliferative potential (109)); 2) the age range of the target population; and 3) the required sample size and length of follow-up (e.g., for one design, assuming a 10 percent rate of noncompliance, it has been estimated that 12,500 women would need to be followed for 5 years to detect a 50 percent reduction in breast cancer risk if the disease rate in untreated women was 3 per 1,000 women (8)).

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