Breast carcinoma chemoprevention in the community setting. Estimating risks and benefits

BACKGROUND: The United States Preventive Services Task Force recommends that women who are at both high risk for breast carcinoma and low risk for adverse events should receive counseling regarding tamoxifen for chemoprevention. Estimates of the risks and benefits of tamoxifen based on results from clinical trials may not reflect the real-world experience. The authors determined the prevalence of women in a community-based cohort who would meet the definition of high risk for breast carcinoma and calculated the number of women needed to screen to determine one for whom the benefits of tamoxifen would outweigh the risks. Baseline incidence also was examined for adverse health events in this community-based cohort compared with participants in the Breast Cancer Prevention Trial. METHODS: The study participants were women ages 40-70 years (n = 6048 women) who were members of the CLUE II cohort, which started in 1989, and who responded to questionnaire surveys in 1996 and 2000. RESULTS: Eighteen percent of all women had a 5-year risk of invasive breast carcinoma > or = 1.66%. The number of women needed to screen to find 1 woman for whom the benefits outweighed the risks of tamoxifen ranged from 26 women ages 40-49 years to 142 women ages 60-70 years. For women who had undergone a hysterectomy, the numbers needed to screen were lower. Baseline incidence rates of fracture and thromboembolic disease were higher in the community-based cohort compared with the rates observed among prevention trial participants; thus, fewer women had to be treated with tamoxifen to prevent one fracture. However, fewer women in the community also had to be treated to observe harm with a thromboembolic event. CONCLUSIONS: Clinicians who counsel women about tamoxifen should take into consideration community-level risks and benefits.     

Women’s decisions regarding tamoxifen for breast cancer prevention: responses to a tailored decision aid

Tamoxifen reduces primary breast cancer incidence, yet causes serious side effects. To date, few women with increased breast cancer risk have elected to use tamoxifen for chemoprevention. The objective of the study was to determine women’s knowledge of and attitudes toward tamoxifen following exposure to a tailored decision aid (DA). A total of 632 women with a 5-year risk of breast cancer ≥1.66% (Mean = 2.56, range = 1.7–17.3) were recruited from two healthcare organizations. Participants viewed an online DA that informed them about their 5-year risk of breast cancer and presented individually tailored content depicting the risks/benefits of tamoxifen prophylaxis. Outcome measures included behavioral intentions (to seek additional information about tamoxifen, to talk to a physician about tamoxifen, and to take tamoxifen); knowledge; and perceived risks and benefits of tamoxifen. After viewing the DA, 29% of participants said they intended to seek more information or talk to their doctor about tamoxifen, and only 6% believed they would take tamoxifen. Knowledge was considerable, with 63% of women answering at least 5 of 6 knowledge questions correctly. Participants were concerned about the risks of tamoxifen, and many believed that the benefits of tamoxifen did not outweigh the risks. This study is the largest to date to test women’s preferences for taking tamoxifen and one of the largest to have tested the impact of a tailored DA. After viewing the DA, women demonstrated good understanding of tamoxifen’s risks and benefits, but most were not interested in taking tamoxifen for breast cancer chemoprevention.     

Breast cancer prevention: a review of current evidence

The National Cancer Institute has created a breast cancer risk assessment tool that quickly estimates a woman's individualized absolute risk of developing breast cancer. Understanding the magnitude of risk is important because recent data show that breast cancer incidence may be reduced. All women may improve their overall health and thus perhaps minimize breast cancer risk by maintaining a healthy weight, avoiding cigarettes, limiting alcohol consumption, getting regular exercise, and avoiding non-diagnostic ionizing radiation. Nevertheless, no lifestyle modifications have yet been proven to prevent or definitively lower the risk of breast cancer. In addition, women whose personal breast cancer risk is high may consider reducing risk by pharmacologic or surgical means. In such women, a five-year course of tamoxifen reduced the risk of invasive breast cancer by 49%; women with lobular carcinoma in situ or atypical hyperplasia experienced even greater risk reductions. Because of the potential for vascular and endometrial side effects, women who are candidates for a preventive course of tamoxifen must be counseled regarding its relative risks and benefits. Prophylactic mastectomy offers at least a 90% reduction in the risk of breast cancer, but the physical and psychological changes involved in such a procedure make it a difficult choice for many women. Breast cancer risk assessment and appropriate counseling are becoming standard components of breast cancer screening and overall health maintenance.     

First do no harm: extending the debate on the provision of preventive tamoxifen.

The Breast Cancer Prevention Trial (BCPT-P-1) demonstrated that tamoxifen could reduce the risk of invasive breast cancer in high-risk women by 49%, but that it could also increase the risk of endometrial cancer, vascular events and cataracts. This paper provides an estimate of the net health impacts of tamoxifen administration on high-risk Canadian women with no prior history of breast cancer. The results of the BCPT-P-1 were incorporated into the breast cancer and other modules of Statistics Canada's microsimulation POpulation HEalth Model (POHEM). While the main intervention scenario conformed as closely as possible to the eligibility criteria for tamoxifen in the BCPT-P-1 protocol, 3 additional scenarios were simulated. Predicted absolute risks of breast cancer at 5 years of 1.66%, 3.32% and 4.15% were calculated for women 35 to 70 years of age. When the BCPT-P-1 results were incorporated into the simulation model, the analysis suggests no increase in life expectancy in this risk group. Tamoxifen appeared to be beneficial for women with a 5-year predicted risk of 3.32% or greater. The results of these simulations are particularly sensitive to the reduction in mortality observed in the BCPT-P-1, as well as being sensitive to other characteristics of the simulation model. Overall, the analysis raises questions about the use of tamoxifen in otherwise healthy women at high risk of breast cancer.     

Impact of tamoxifen adjuvant therapy on symptoms, functioning, and quality of life.

This article reviews the symptoms and everyday problems associated with tamoxifen adjuvant therapy and their impact on patients' quality of life. In addition, the purported toxic effects of tamoxifen therapy (e.g., premature menopause, weight gain, and depression) are discussed, and data are presented that refute claims of the toxicity of tamoxifen therapy. From randomized controlled trials of adjuvant therapy, we know that tamoxifen therapy increases the rate of hot flashes, night sweats, and vaginal discharge; however, in observational studies these symptoms do not have a statistically significant impact on patients' quality of life as measured by standardized, self-report questionnaires. The Breast Cancer Prevention Trial found no evidence of excessive rates of depression or clinically significant differences in sexual functioning between women receiving placebo and those receiving tamoxifen therapy. Although several serious medical risks from tamoxifen therapy exist (e.g., uterine cancer, blood clots, stroke, and cataracts), there are additional benefits from tamoxifen therapy in addition to an increase in disease-free survival rates and overall survival rates, including a decrease in contralateral breast cancer and fractures. Ultimately, the decision to receive tamoxifen therapy is a personal choice for each woman to make on the basis of the evidence of tamoxifen therapy's benefits and risks, along with her own motivation to receive therapy. When the benefits of such therapy are small, some women may choose to avoid treatment, but others may wish to try therapy to determine whether possible side effects are relevant. For women in whom the absolute survival benefits are large, there may be less difficulty in making this decision.     

Tamoxifen in Axillary Node-Negative Breast Cancer: Multisystem Benefits and Risks

Adjuvant tamoxifen therapy is associated with modest improvement in disease-free and overall survival in women with invasive axillary node-negative breast cancer. The preponderance of data supporting these general conclusions are from trials in postmenopausal women; in premenopausal women data appear convincing regarding disease-free, hut not overall, survival. Firm conclusions regarding magnitude of benefit related to presence of different prognostic factors cannot be drawn at present.

In postmenopausal women tamoxifen appears to alter favorably some risk factors for cardiovascular diseases and osteoporosis, which are the most common causes of mortality or morbidity in older American women. Adjuvant tamoxifen is associated with a significantly reduced risk of second primary breast cancer. Major serious risks of tamoxifen therapy include depression, and possibly thrombophlebitis and uterine endometrial cancer. Symptomatic vasomotor and gynecological side effects are frequent. Decision making with women should include assessment of these multisystem benefits and risks.     

Breast cancer chemoprevention

According to the National Cancer Institute Surveillance Epidemiology and End Results Cancer Statistics Review, the incidence of invasive breast cancer in the USA is 124 women per 100,000 population. Women at increased risk for breast cancer have three major options to reduce their risk, specifically screening, chemoprevention and prophylactic surgery. In this article, we focus on chemoprevention. There are three chemoprevention agents available to reduce breast cancer risk: tamoxifen, raloxifene and exemestane. In this article, we summarize the major randomized clinical trials investigating the use of these agents in the chemoprevention setting. Randomized controlled trials have shown that these agents can reduce breast cancer incidence, but the potential risks of these agents and their impact on quality of life should also be carefully considered. Indeed, it is always important to keep in mind that chemoprevention targets asymptomatic women, and therefore the decision to embark on this strategy should never be taken lightly.     

Outcomes of tamoxifen chemoprevention for breast cancer in very high-risk women: a cost-effectiveness analysis.

PURPOSE: To estimate the effects on survival, quality-adjusted survival, and health care costs of using tamoxifen for primary prevention in subgroups of women at very high risk for breast cancer. PATIENTS AND METHODS: A decision analysis was performed using a hypothetical cohort of women that included subgroups with atypical hyperplasia, Gail risk greater than 5, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. Data sources were the Breast Cancer Prevention Trial, the Surveillance, Epidemiology, and End-Results program, time trade-off preference ratings, the Group Health Cooperative of Puget Sound, and the United States Health Care Financing Administration. RESULTS: Our model predicted that tamoxifen would prolong the average survival of cohort members initiating use at ages 35, 50, and 60 years by 70, 42, and 27 days, respectively. It would prolong survival even more for those in the higher-risk groups, especially those with atypical hyperplasia (202, 89, and 45 days). Tamoxifen use was also projected to extend quality-adjusted survival by 158, 80, and 50 days in the atypical hyperplasia group. For younger women in the highest risk groups, chemoprevention with tamoxifen was estimated to have cost savings or be cost-effective, both with and without quality adjustments. CONCLUSION: Chemoprevention with tamoxifen may be particularly beneficial to women with atypical hyperplasia, 5-year Gail model risk greater than 5%, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. The benefits may be greater if tamoxifen is initiated before age 50 years rather than after and if the breast cancer risk reduction conferred by tamoxifen lasts longer than 5 years. For women with a very high risk of invasive breast cancer, chemoprevention with tamoxifen seems to be cost-effective.     

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.     

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.     

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.     

Patient preferences for axillary dissection in the management of early-stage breast cancer

BACKGROUND: Recent data on the value of adjuvant therapy in lymph node-negative breast cancer and promising early data on less invasive strategies for managing the axilla have raised questions about the appropriate role of axillary lymph node dissection (ALND) in the management of early-stage breast cancer. We sought to evaluate how women weigh potential benefits of ALND-prognostic information, enhanced local control, and tailored therapy-against the risks of long-term morbidity that are associated with the procedure. METHODS: We used hypothetical scenarios to survey 82 randomly selected women with invasive breast cancer who had been treated with ALND and 62 women at risk for invasive breast cancer by virtue of a history of ductal carcinoma in situ (DCIS) who had not undergone ALND. RESULTS: Women in both the invasive cancer and the DCIS groups required substantial improvements in local control of the cancer (5% and 15%, respectively) and overall survival (3% and 10%, respectively) before they would opt for this procedure. Women with invasive cancer would choose ALND if it had only a 1% chance of altering treatment recommendations, whereas DCIS subjects required a 25% chance. Sixty-eight percent and 29% of women in the invasive cancer and DCIS groups, respectively, would accepted a 40% risk of arm dysfunction to gain prognostic information that would not change treatment. CONCLUSIONS: For most subjects treated previously for invasive breast cancer and almost half those at risk of the disease, the potential benefits of ALND, particularly the value of prognostic information, were sufficient to outweigh the risks of morbidity. However, women varied considerably in their preferences, highlighting the need to tailor decisions regarding management of the axilla to individual patients' values.     

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.     

American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition.

OBJECTIVE: To update an evidence-based technology assessment of chemoprevention strategies for breast cancer risk reduction. POTENTIAL INTERVENTIONS: Tamoxifen, raloxifene, aromatase inhibition, and fenretinide. OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefit. EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO) prescribed technology assessment procedure was followed. VALUES: More weight was given to published randomized trials. BENEFITS/HARMS: A woman's decision regarding breast cancer risk reduction strategies is complex and will depend on the importance and weight attributed to information regarding both cancer- and noncancer-related risks and benefits. CONCLUSIONS: For women with a defined 5-year projected breast cancer risk of > or= 1.66%, tamoxifen (at 20 mg/d for 5 years) may be offered to reduce their risk. Risk/benefit models suggest that greatest clinical benefit with least side effects is derived from use of tamoxifen in younger (premenopausal) women (who are less likely to have thromboembolic sequelae and uterine cancer), women without a uterus, and women at higher breast cancer risk. Data do not as yet suggest that tamoxifen provides an overall health benefit or increases survival. In all circumstances, tamoxifen use should be discussed as part of an informed decision-making process with careful consideration of individually calculated risks and benefits. Use of tamoxifen combined with hormone replacement therapy or use of raloxifene, any aromatase inhibitor or inactivator, or fenretinide to lower the risk of developing breast cancer is not recommended outside of a clinical trial setting. This technology assessment represents an ongoing process and recommendations will be updated in a timely matter. VALIDATION: The conclusions were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors.     

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.     

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.     

Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor--positive breast cancer.

PURPOSE: To investigate the patterns and predictors of tamoxifen discontinuance throughout a 2-year period in a cohort of women 65 years or older with newly diagnosed, estrogen receptor (ER)-positive breast cancer, focusing on the role of patients' beliefs about the risks and benefits of tamoxifen therapy. SUBJECTS AND METHODS: We enrolled a convenience sample of women cared for in four geographic regions of the United States with stage 1 (>/= 1 cm), stage II, or stage IIIA disease; no prior history of breast cancer; and no simultaneously diagnosed second primary breast cancer. Data sources included medical records and telephone interviews with patients at 3, 6, 15, and 27 months following definitive surgery. RESULTS: Of the 597 women with ER-positive tumors, 516 women (86%) were prescribed tamoxifen, and of these, 88 (17%) stopped taking tamoxifen during the 2-year follow-up period. Of the women who stopped taking tamoxifen, the majority (68%) took it for less than 1 year. Women with neutral or negative beliefs about the value of tamoxifen (3.0; 95% CI, 1.6 to 5.6) and those with positive nodes (odds ratio = 2.5; 95% CI, 1.0 to 6.3) were more likely to discontinue tamoxifen therapy. CONCLUSION: How women with early-stage breast cancer perceive the risks and benefits of tamoxifen therapy seems critical for sustaining adherence to adjuvant tamoxifen therapy. Interventions designed to educate women about the benefits and risks of tamoxifen therapy may help to reduce discontinuance.     

The role of aromatase inhibitors in early breast cancer

Opinion statement The role of hormonal therapy for the treatment of patients with early stage breast cancer has been evaluated in many studies. The results of these studies establish tamoxifen as the gold standard of hormonal therapy for the adjuvant treatment of hormone receptorpositive invasive breast cancer in pre- and postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast cancer in women at increased risk for the disease, including women with ductal carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased risk of uterine cancer in postmenopausal women, and rare occurrence of thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen, alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic activity. AIs function by inhibiting the peripheral conversion of adrenally synthesized androstenedione to estradiol through inhibition of the aromatase enzyme. AIs do not suppress estradiol synthesis by the ovary adequately. Therefore, AIs are effective in reducing circulating estradiol levels in postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin; Pharmacia, Peapack, NJ) have been associated with increased specificity and improved therapeutic index compared to nonselective AIs such as aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be superior to megestrol acetate in second-line therapy of postmenopausal women with metastatic breast cancer, and selective nonsteroidal AIs have shown to be superior to tamoxifen in first-line therapy of postmenopausal women with metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in combination) trial is the only published randomized trial comparing the efficacy of an AI to tamoxifen for the adjuvant treatment of women with early breast cancer. This large study showed that at a median follow-up time of 33 months, anastrozole alone results in significant improvement in disease-free survival rates, reduction in contralateral breast cancers, and increased tolerability, compared to tamoxifen in postmenopausal women. Although the long-term effects of AIs are not known, the early positive results of the ATAC trial led to the approval of anastrozole by the US Food and Drug Administration for use as adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive invasive breast cancer. Thus, there is an alternative to tamoxifen for postmenopausal women with relative/absolute contraindications to tamoxifen use or patients who choose not to take tamoxifen because of its side-effect profile. New AIs may challenge the position of tamoxifen as the gold standard for the treatment of early stage breast cancer in postmenopausal women.     

The impact of systemic therapy following ductal carcinoma in situ

Following local therapy for ductal carcinoma in situ (DCIS), tamoxifen reduces the risk of ipsilateral and contralateral breast cancer by 30%-50%. Studies of tamoxifen in women with resected DCIS have not shown any effect on overall or cancer-specific survival. The adverse event profile of tamoxifen is well characterized, and individual risks and benefits should be assessed to guide decision making. We review the results of the phase III trials of tamoxifen in DCIS as well as the emerging risk reduction therapies.     

Anti-oestrogenic chemoprevention of breast cancer-the need to progress

Clinical trials of the selective oestrogen receptor modulator (SERM), tamoxifen, have shown an early reduction in risk of breast cancer in healthy women of approximately 40%, but with associated risks and benefits to normal tissues. An overall clinical benefit and the identification of the women at risk of breast cancer who may gain benefit from tamoxifen has not been clearly established. The identification of those women at risk who are most likely to gain benefit, and the development of other SERMs and aromatase inhibitors which might be more active and have a more beneficial spectrum of activity on normal tissues in healthy women is essential, if the aim of preventing breast cancer in healthy women is to be achieved.