Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention

BACKGROUND: The Breast Cancer Prevention Trial demonstrated that tamoxifen treatment produced a 49% reduction in the risk of invasive breast cancer among women at elevated risk for the disease. The U.S. Food and Drug Administration (FDA) subsequently approved tamoxifen for women aged 35 years or older with a 5-year breast cancer risk of 1.67% or higher for breast cancer chemoprevention. However, tamoxifen use has been associated with adverse outcomes, and not all eligible women have a positive benefit/risk ratio. METHODS: We used weighted data from the year 2000 National Health Interview Survey Cancer Control Module to estimate the total number of U.S. women, aged 35-79 years, who were eligible for tamoxifen chemoprevention based on the FDA eligibility criteria. We also estimated the numbers of white and black women who would benefit from tamoxifen chemoprevention on the basis of a positive benefit/risk index developed by Gail et al. RESULTS: Of the 65,826,074 women aged 35-79 years without reported breast cancer in the United States in 2000, 10,232 816 women (15.5%, 95% confidence interval [CI] = 14.7% to 16.3%) would be eligible for tamoxifen chemoprevention. The percentage of U.S. women who would be eligible varied dramatically by race, with 18.7% (95% CI = 17.8% to 19.7%) of white women, 5.7% (95% CI = 4.3% to 7.5%) of black women, and 2.9% (95% CI = 2.1% to 3.9%) of Hispanic women being eligible. Of the 50,104,829 white U.S. women aged 35-79 years, 2,431,911 (4.9%, 95% CI = 4.3% to 5.4%) would have a positive benefit/risk index for tamoxifen chemoprevention. Of the 7,481,779 black U.S. women aged 35-79 years, only 42,768 (0.6%, 95% CI = 0.2% to 1.3%) would have a positive benefit/risk index. Among white women, 28,492 (95% CI = 24,693 to 32,292) breast cancers would be prevented or deferred if those women who have a positive net benefit index took tamoxifen over the next 5 years. CONCLUSION: A substantial percentage of U.S. women would be eligible for tamoxifen chemoprevention according to FDA criteria, but a much smaller percentage would have an estimated net benefit. Nevertheless, this latter percentage corresponds to more than two million women.     

Breast Cancer Prevention

Although screening recommendations have been long established, more than 40 000 women died of breast cancer in the US in the year 2001. Risk factors for developing breast cancer have been identified, leading to the possibility of breast cancer prevention. Adjuvant tamoxifen for 5 years decreases the incidence of contralateral breast cancer by 50%. This finding and the favorable safety profile of tamoxifen led to the NSABP P-1 trial, which demonstrated a 50% reduction of breast cancer in a high-risk population. The benefit was seen only in estrogen receptor (ER)-positive breast cancers, but was seen in all age groups. Furthermore, tamoxifen was found to reduce the overall rate of osteoporotic fractures. Endometrial cancer in the tamoxifen arm of the NSABP P-l trial was increased 3- to 4-fold in women >50 years, similar to the increased risk seen with adjuvant tamoxifen therapy. Other agents that are currently under study for breast cancer chemoprevention include raloxifene and retinoids. The STAR trial is under way and compares raloxifene to tamoxifen for breast cancer chemoprevention in high-risk women. Tamoxifen is currently the only agent approved by the US Food and Drug Administration (FDA) for chemoprevention in breast cancer but has not produced a survival advantage to date.     

Chemoprevention of breast cancer

Despite a recent trend toward improvement in the U.S. breast cancer mortality rate, breast cancer incidence (182,800 new cases anticipated in 2000) and mortality figures (over 40,800 anticipated deaths) remain the highest and second highest, respectively, of all cancers in U.S. women. In 1998, the selective-estrogen-receptor-modulator (SERM) tamoxifen achieved positive results in the Breast Cancer Prevention Trial (BCPT), leading to the Food and Drug Administration (FDA) approval of tamoxifen for risk reduction in women at high risk of breast cancer (the historic first FDA approval of a cancer preventive agent). This brought about a paradigm shift in new approaches for controlling breast cancer toward pharmacologic preventive regimens, called chemoprevention. This paper presents a comprehensive clinical review of breast cancer prevention study, highlighting issues of the extensive study of tamoxifen. These issues include the record of primary tamoxifen results in several breast-cancer risk-reduction settings (primary, adjuvant, and ductal carcinoma in situ [DCIS]); critical secondary BCPT risk-benefit findings (including quality of life issues) and their effects on counseling patients on use of tamoxifen for prevention; ethic minorities; optimal tamoxifen dose/duration; and potential impact on mortality and other issues involved with potential net benefit to society. Other breast-cancer chemoprevention issues reviewed here include women at high genetic risk (especially BRCA1 mutation carriers); raloxifene in breast cancer prevention; other SERMs; SERM resistance; and new agents and combinations currently in development. Very recent developments involving PPAR- ligands, COX-2 inhibitors, and RXR-ligands are discussed in the section on new drug development.     

The STAR trial: evidence for raloxifene as a breast cancer risk reduction agent for postmenopausal women

The 1998 approval of tamoxifen for breast cancer risk reduction opened the era of breast cancer chemoprevention. Women at increased risk for breast cancer now had an option other than healthy lifestyle and prophylactic surgery to reduce risk. However, women and their physicians were reluctant to use tamoxifen because of associated risks. Several trials investigating raloxifene suggested it may reduce breast cancer risk without having an apparent effect on the endometrium. The Study of Tamoxifen and Raloxifene (STAR) for the Prevention of Breast Cancer trial opened in 1999 to directly compare raloxifene to tamoxifen for breast cancer risk reduction. Since the unblinding of the STAR trial in 2006, raloxifene has emerged as an option for reducing breast cancer risk for postmenopausal women at increased risk for the disease.     

Economic evaluation of chemoprevention of breast cancer with tamoxifen and raloxifene among high-risk women in Japan

Raloxifene was approved for chemoprevention against breast cancer among high-risk women in addition to tamoxifen by the US Food and Drug Administration. This study aims to evaluate cost-effectiveness of these agents under Japan''s health system. A cost-effectiveness analysis with Markov model consisting of eight health states such as healthy, invasive breast cancer, and endometrial cancer is carried out. The model incorporated the findings of National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 trial, and key costs obtained from health insurance claim reviews. Favourable results, that is cost saving or cost-effective, are found by both tamoxifen and raloxifene for the introduction of chemoprevention among extremely high-risk women such as having a history of atypical hyperplasia, a history of lobular carcinoma in situ or a 5-year predicted breast cancer risk of ⩾5.01% starting at younger age, whereas unfavourable results, that is ‘cost more and gain less'' or cost-ineffective, are found for women with a 5-year predicted breast cancer risk of ⩽5.00%. Therapeutic policy switch from tamoxifen to raloxifene among postmenopausal women are implied cost-effective. Findings suggest that introduction of chemoprevention targeting extremely high-risk women in Japan can be justifiable as an efficient use of finite health-care resources, possibly contributing to cost containment.     

Update on breast cancer prevention

Four randomized prospective trials have evaluated tamoxifen for chemoprevention of breast cancer. The National Surgical Adjuvant Breast and Bowel Project P-1 trial reported that tamoxifen reduced the risk of invasive breast cancer by 49%. Two smaller European trials, the Royal Marsden Hospital Chemoprevention Trial and the Italian Tamoxifen Prevention Study, demonstrated no decrease in the incidence of breast cancer among women using tamoxifen. The International Breast Cancer Intervention Study confirmed that tamoxifen can reduce the risk of breast cancer in healthy women. The Multiple Outcomes of Raloxifene Evaluation trial, which evaluated the use of raloxifene (Evista) to prevent osteoporosis, found that the risk of invasive breast cancer decreased by 76%. A uniform theme in these trials is that tamoxifen reduces the risk of breast cancer among women at high risk for the disease. Tamoxifen is currently approved for breast cancer risk reduction. However, because of the side effects associated with its use (i.e., endometrial cancer and thromboembolism), other agents are being investigated. The Study of Tamoxifen and Raloxifene is designed to compare the efficacy of tamoxifen and raloxifene in reducing breast cancer risk. Aromatase inhibitors will also be studied in the setting of chemoprevention for breast cancer.     

Aromatase inhibitors for the treatment and prevention of breast cancer

In a review of current information on aromatase inhibitors (AIs) and their use in breast cancer treatment and prevention, published reports were obtained through a Medline search. Tamoxifen, a selective estrogen receptor modulator, is approved for use in metastatic breast cancer (MBC), the adjuvant treatment of breast cancer, and the prevention of breast cancer in women at high risk. The 50% reduction in breast cancer incidence seen with tamoxifen is significant for women at increased risk but is accompanied by notable toxicities such as thrombotic events and endometrial cancer. Therefore, the development of other effective agents with less toxicity would be a major advance in breast cancer prevention. Aromatase inhibitors, recently approved for the treatment of MBC and in the adjuvant setting, are proving to be slightly more effective than tamoxifen therapy. These drugs, approved for use in only postmenopausal women, inhibit the enzyme aromatase and thereby lower circulating functional estrogen. To date, the most concerning side effect of these agents is an increase in fracture rate. Compared with tamoxifen, thrombotic events and endometrial cancer rates are much lower. Ongoing data from the Arimidex, Tamoxifen, Alone or in Combination trial continue to favor anastrozole over tamoxifen in the reduction of primary contralateral breast cancers. This information has prompted breast cancer chemoprevention trials with AIs. Although tamoxifen is the gold standard for prevention therapy, results of ongoing studies may indicate a role for AIs in the prevention of breast cancer.     

Continued Breast Cancer Risk Reduction in Postmenopausal Women Treated with Raloxifene: 4-Year Results from the MORE Trial

Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis. This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial. Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board. A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60mg/day, and 2,572 raloxifene 120mg/day. Women were a mean of 66.5-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures). As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30). Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0.003). We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both. Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer.     

Chemoprevention Strategies 2006

Opinion statement Several large, prospective trials have evaluated tamoxifen compared with placebo for breast cancer risk reduction in women at increased risk for breast cancer. The risk of developing breast cancer is the primary determinant of net benefit, with greater net benefits accruing to women with the highest risk of breast cancer. Both age and the presence of factors that increase the risk of toxicity have the greatest effect on the net benefit associated with tamoxifen. The greatest clinical benefit with least side effects is derived from the use of tamoxifen in younger, premenopausal women who are less likely to have thromboembolic complications and uterine cancer, in women without a uterus, and in women at higher breast cancer risk such as those with atypical hyperplasia or lobular carcinoma in situ. Tamoxifen may offer benefit to women who are carriers of BRCA2 mutations, although no prospective trials have been conducted. Compared to placebo in postmenopausal women at average risk of breast cancer in published trials of osteoporosis, raloxifene reduces the risk of invasive breast cancer. Among younger postmenopausal women who are at increased risk of breast cancer, raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. Raloxifene appears to be less effective than tamoxifen in reducing the risk of in situ breast cancer. In high-risk, younger, postmenopausal women, raloxifene appears to offer net benefit when comparing reduction of the risk of breast cancer and the prevention of fractures with the risk of stroke, venous thromboembolic events, uterine events, as well as symptomatic side effects.     

Application of selective estrogen receptor modulators for breast cancer treatment according to their intrinsic nature

The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene exert their estrogen agonist and antagonist actions depending on the target organ and individual circumstances. For instance, tamoxifen increases bone mineral density in postmenopausal patients, but decreases it in premenopausal patients when it is used as the adjuvant therapy for breast cancer in both populations. Due to positive results from recent large clinical trials for early breast cancer, the aromatase inhibitors (AIs) are the agent of first choice for postmenopausal patients. However, the veteran SERM tamoxifen is still the primary drug for premenopausal breast cancer patients, patients with ductal carcinoma in situ and subset of postmenopausal women. Recent accumulated data suggest that both raloxifene and tamoxifen could be useful in chemoprevention. Further investigation should be made into the development of a systematic strategy for application to a suitable target population, i.e., one more likely to develop hormone receptor-positive breast cancer. Unlike the AIs, SERMs have a distinct function that does not directly relate to hormone receptors when used in higher pharmacological concentration. The attempt to overcome chemo-drug resistance using high-dose SERMs would be one approach to developing such a strategy. There were several reports showing the antiproliferative effect of SERMs for estrogen receptor-negative cells, such as glioma. There are still numerous possible applications for SERMs when their intrinsic nature is utilized.     

The role of selective estrogen receptor modulators in the prevention of breast cancer: comparison of the clinical trials

The role of estrogen in the development of breast cancer is well recognized, and the use of selective estrogen receptor modulators (SERMs) to reduce breast cancer risk continues to be evaluated. Tamoxifen is the only SERM approved for the reduction of breast cancer incidence in women at high risk. This approval was based on results from the Breast Cancer Prevention Trial. Although initial results from the Royal Marsden Hospital tamoxifen trial and Italian Tamoxifen Prevention Study did not show a similar overall effect of tamoxifen, recent updates from these two trials and initial results from the International Breast Cancer Intervention Study are consistent with a risk reduction effect of tamoxifen for estrogen-receptor-positive breast cancer. Raloxifene, approved for the prevention and treatment of postmenopausal osteoporosis, is another SERM being evaluated for breast cancer risk reduction. The recently completed Continuing Outcomes Relevant to Evista trial and the Raloxifene Use for The Heart trial, have breast cancer risk reduction as a primary end point. A third, ongoing trial, the Study of Tamoxifen and Raloxifene trial, is evaluating the relative efficacy and adverse event profile of these two agents in a population at high risk. The study populations of these raloxifene breast cancer prevention trials and the four tamoxifen prevention trials are quite diverse in terms of breast cancer risk. Completion of these trials will provide important information about the occurrence of invasive breast cancer in postmenopausal women and the efficacy of raloxifene for breast cancer risk reduction.     

Selective oestrogen receptor modulators/new antioestrogens: a clinical perspective

Following tamoxifen, the first selective oestrogen receptor modulator (SERM), a number of other antioestrogens have been developed. The first-generation SERMs exhibit cross-resistance with tamoxifen and have agonist effects on the uterus. Toremifene has equal efficacy to tamoxifen and may be useful as a tamoxifen alternative. Efficacy results for droloxifene and idoxifene were disappointing and their clinical development ceased. Response rates for second-generation SERMs such as raloxifene and arzoxifene are also not high, although raloxifene shows promise in the chemoprevention of breast cancer. Paradoxically, high-dose oestrogens are proving to be effective breast cancer treatment with similar responses to tamoxifen in postmenopausal women with advanced disease, although these drugs are not well tolerated. Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist effects, which binds, blocks and degrades the ER. Fulvestrant produces high response rates compared with the SERMs, is not cross-resistant with SERMs or aromatase inhibitors (AIs) and is equally as effective as the AI anastrozole in the treatment of postmenopausal women with advanced breast cancer who have progressed after prior antioestrogen therapy. Pure antioestrogens such as the ER antagonist fulvestrant provide opportunities for therapeutic sequencing with tamoxifen and AIs and offer exciting possibilities for the future treatment of breast cancer.     

Prevention with tamoxifen or other hormones versus prophylactic surgery in BRCA1/2-positive women: a decision analysis

PURPOSE: Recent randomized controlled trials have shown that tamoxifen and raloxifene may prevent invasive breast cancer. This decision analysis study compares the outcomes of chemoprevention with tamoxifen, raloxifene, or oral contraceptives with the outcomes of prophylactic surgery among women with high-risk BRCA1/2 mutations. PATIENTS AND METHODS: We used a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations and constructed a Markov model with Monte Carlo simulations, incorporating cumulative breast and ovarian cancer incidence rates from the literature and survival figures from SEER data. We assumed that prophylactic surgery reduces ovarian cancer risk by 45% and breast cancer risk by 90%, that tamoxifen reduces invasive breast cancer risk by 49%, and that raloxifene has similar efficacy and safety in premenopausal and postmenopausal women. We used data obtained from high-risk women by a time trade-off questionnaire to calculate quality-adjusted life-years. We based our cost estimates for hospital and ambulatory care on Health Care Financing Administration payments, the SEER-HCFA database, and the Pharmacy Fundamental Reference. RESULTS: In our model, a 30-year-old BRCA1/2+ woman could prolong survival by 0.9 years (95% probability interval, 0.4-1.2 years) by having bilateral oophorectomy, 3.4 years (2.7-3.7 years) by having bilateral mastectomy, and 4.3 years (3.6-4.6 years) by having both procedures instead of surveillance alone. Chemoprevention with tamoxifen and raloxifene increased survival by 1.6 years (1.0-2.1 years) and 2.2 years (1.3-2.8 years), respectively. Chemoprevention yielded more quality-adjusted life-years than did prophylactic surgery, even when treatment was delayed to age 40 or 50 years. All these procedures were cost-effective or cost-saving compared with surveillance alone. DISCUSSION: Our model suggests that although surgery may yield more substantial survival and cost benefits, quality of life issues may make chemoprevention a more attractive option for young women at high genetic risk.     

Women��s interest in taking tamoxifen and raloxifene for breast cancer prevention: response to a tailored decision aid

Although tamoxifen can prevent primary breast cancer, few women use it as a preventive measure. A second option, raloxifene, has recently been approved. The objective of the study was to determine women's interest in tamoxifen and raloxifene after reading a decision aid (DA) describing the risks and benefits of each medication. Women with 5-year risk of breast cancer ≥ 1.66 from two large health maintenance organizations were randomized to receive a DA versus usual care. After reading an on-line DA that discussed the risks and benefits of tamoxifen and raloxifene, women completed measures of risk perception, decisional conflict, behavioral intentions, and actual behavior related to tamoxifen and raloxifene. 3 months following the intervention, 8.1% of participants had looked for additional information about breast cancer prevention drugs, and 1.8% had talked to their doctor about tamoxifen and/or raloxifene. The majority, 54.7%, had decided to not take either drug, 0.5% had started raloxifene, and none had started tamoxifen. Participants were not particularly worried about taking tamoxifen or raloxifene and did not perceive significant benefits from taking these drugs. Over 50% did not perceive a change in their risk of getting breast cancer if they took tamoxifen or raloxifene. After reading a DA about tamoxifen and raloxifene, few women were interested in taking either breast cancer prevention drug.     

Raloxifene for the treatment and prevention of breast cancer?

Raloxifene is a member of a family of drugs known as selective estrogen receptor modulators (SERMs). Raloxifene is currently approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. SERMs hold the potential to treat and prevent breast cancer, osteoporosis and coronary heart disease. Ongoing clinical trials are in place to address the role of raloxifene and SERMs in each of these areas. We review the pharmacology, clinical utility, safety and tolerability of raloxifene and speculate on what the future holds for SERMs and their use in breast cancer.     

Selective estrogen-receptor modulators in 2001

Tamoxifen (Nolvadex), a selective estrogen-receptor modulator, or SERM, is currently the endocrine therapy of choice for all stages of hormone-responsive breast cancer. Only tamoxifen has been approved by the US Food and Drug Administration to reduce the incidence of breast cancer in high-risk women. Despite tamoxifen's antiestrogenic effects in breast tissue, it exhibits paradoxical estrogenic effects in other tissues in the body. These effects result in the maintenance of bone mineral density, but a three- to fourfold increase in endometrial cancer in postmenopausal women. Additionally, tamoxifen can result in troublesome hot flashes and serious thromboembolic events. For this reason, current research is focusing on new agents that may maintain the beneficial effects of tamoxifen while reducing its adverse effects. Raloxifene (Evista) is another SERM, approved for the prevention of osteoporosis in postmenopausal women and now being compared with tamoxifen in an ongoing breast cancer prevention trial. Like tamoxifen, raloxifene is associated with hot flashes and thromboembolic events, but its association with the risk of endometrial cancer is unknown. A number of new SERMs are in preclinical or clinical development in an attempt to improve upon the safety profile of tamoxifen. Additionally, selective aromatase inhibitors are being examined in the early breast cancer setting.     

Update on raloxifene to prevent endometrial-breast cancer

In the mid 1980s when tamoxifen was shown to be associated with endometrial neoplasia there was a renewed interest in another SERM compound, raloxifene. Experimental animal data suggested that raloxifene did not stimulate the endometrium as tamoxifen does while having similar anti-oestrogenic effects in breast tissue as tamoxifen. Clinical data has now shown that raloxifene does not stimulate the endometrium in postmenopausal women. It results in no hyperplasia, no increase in endometrium thickness or polyp formation and virtually no proliferation. Further studies are necessary to see if long-term raloxifene use will reduce the risk of endometrial cancer. In studies of raloxifene as treatment for osteoporosis, when viewed as a secondary endpoint there was a significant reduction in risk of new onset breast cancer. Further studies with breast cancer as a primary endpoint are ongoing (the STAR Trial).     

Raloxifene for the treatment and prevention of breast cancer?

Raloxifene is a member of a family of drugs known as selective estrogen receptor modulators (SERMs). Raloxifene is currently approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. SERMs hold the potential to treat and prevent breast cancer, osteoporosis and coronary heart disease. Ongoing clinical trials are in place to address the role of raloxifene and SERMs in each of these areas. We review the pharmacology, clinical utility, safety and tolerability of raloxifene and speculate on what the future holds for SERMs and their use in breast cancer.     

American Society of Clinical Oncology technology assessment on breast cancer risk reduction strategies: tamoxifen and raloxifene.

OBJECTIVE: To conduct an evidence-based technology assessment to determine whether tamoxifen and raloxifene as breast cancer risk-reduction strategies are appropriate for broad-based conventional use in clinical practice. POTENTIAL INTERVENTION: Tamoxifen and raloxifene. OUTCOME: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefits. EVIDENCE: A comprehensive, formal literature review was conducted for tamoxifen and raloxifene on the following topics: breast cancer risk reduction; tamoxifen side effects and toxicity, including endometrial cancer risk; tamoxifen influences on nonmalignant diseases, including coronary heart disease and osteoporosis; and decision making by women at risk for breast cancer. Testimony was collected from invited experts and interested parties. VALUES: More weight was given to publications that described randomized trials. BENEFITS/HARMS/COSTS: The American Society of Clinical Oncology (ASCO) Working Group acknowledges that a woman's decision regarding breast cancer risk-reduction strategies will depend on the importance and weight attributed to the information provided regarding both cancer and non-cancer-related risks. CONCLUSIONS: For women with a defined 5-year projected risk of breast cancer of >/= 1.66%, tamoxifen (at 20 mg/d for up to 5 years) may be offered to reduce their risk. It is premature to recommend raloxifene use to lower the risk of developing breast cancer outside of a clinical trial setting. On the basis of available information, use of raloxifene should currently be reserved for its approved indication to prevent bone loss in postmenopausal women. Conclusions are based on single-agent use of the drugs. At the present time, the effect of using tamoxifen or raloxifene with other medications (such as hormone replacement therapy), or using tamoxifen and raloxifene in combination or sequentially, has not been studied adequately. The continuing use of placebo-controlled trials in other risk-reduction trials highlights the current unanswered issues concerning the use of such interventions, especially when the influence on net health benefit remains to be determined. Breast cancer risk reduction is a rapidly evolving area. This technology assessment represents an ongoing process with existing plans to monitor and review data and to update recommendations in a timely matter. (See VALIDATION: The conclusions of the Working Group were evaluated by the ASCO Health Services Research Committee and by the ASCO Board of Directors. SPONSOR: American Society of Clinical Oncology.     

Breast cancer prevention trials

A new option for women at increased risk for breast cancer is chemoprevention—namely, an attempt to decrease breast cancer incidence by means of drug therapy. The efficacy of tamoxifen as a chemopreventive agent has been studied to date in three randomized, controlled trials, with varying results. Investigators with the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial found that tamoxifen reduced the incidence of breast cancer by almost half, whereas British and Italian researchers found no significant benefit. This disparity is due, in part, to differences in the baseline breast cancer risk characteristics among the study populations, differing cohort sizes, variable use of hormone replacement therapy, and other factors. In this article, we review the eligibility criteria, treatment plans, and results from the three published randomized trials of tamoxifen versus placebo. We also review the data on raloxifene and breast cancer incidence. Chemoprevention with tamoxifen, in a non-study setting, is one option for women at increased risk for breast cancer. The ongoing Study of Tamoxifen and Raloxifene (STAR) is a randomized, doubleblinded trial comparing the effectiveness of raloxifene with that of tamoxifen in postmenopausal women at increased risk for developing breast cancer. Until the results of this trial are available, it is premature to use raloxifene for primary breast cancer prevention.