Population-based Study of Prosigna-PAM50 and Outcome Among Postmenopausal Women With Estrogen Receptor-positive and HER2-negative Operable Invasive Lobular or Ductal Breast Cancer.

PURPOSE: The Prosigna-PAM50 risk of recurrence (ROR) score has documented clinical utility for the prediction of 10-year distant recurrence (DR). The present study investigated the value of Prosigna-PAM50 for predicting 10-year DR and overall survival after 5 years of endocrine treatment for postmenopausal patients with invasive lobular carcinoma. PATIENTS AND METHODS: Using the Danish Breast Cancer Group database, we identified patients with a diagnosis from 2000 to 2003 of estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal (n = 1570) or lobular (n = 341) cancer > 20 mm or 1 to 3 positive lymph nodes and applied multivariate Cox models. RESULTS: The median follow-up for DR was 9.3 years and for overall survival 15.2 years. Of the 341 lobular and 1570 ductal cases, 140 (41%) and 349 (22%) were classified as low ROR, with a 10-year DR rate of 7.7% (95% confidence interval [CI], 3.7%-13.6%) and 3.5% (95% CI, 1.8%-6.2%), respectively. The 10-year DR rate for the intermediate ROR group for those with lobular cancer was 18% (95% CI, 10.1%-27.9%) compared with 9.7% (95% CI, 6.7%-13.4%) for those with ductal cancer. Luminal B tumors had a significantly worse outcome than luminal A tumors in both lobular (hazard ratio, 1.89; 95% CI, 1.03%-3.45%; P = .04) and ductal (hazard ratio, 3.18; 95% CI, 2.29%-4.43%; P < .0001) cancer. CONCLUSION: Prosigna PAM-50 provides significant prognostic information beyond the clinicopathologic factors in patients with invasive lobular breast cancer. Those with lobular cancer had worse 10-year DR rates compared with those with ductal cancer in the same ROR category. Our results could have an effect on the treatment decisions regarding the addition of chemotherapy for those in the intermediate ROR group.

Chemoprevention Uptake for Breast Cancer Risk Reduction Varies by Risk Factor.

BACKGROUND/OBJECTIVE: The efficacy of chemoprevention for breast cancer risk reduction has been demonstrated in randomized controlled trials; however, use remains low. We sought to determine whether uptake differed by risk factors, and to identify reasons for refusal and termination. METHODS: Women seen in a high-risk clinic from October 2014 to June 2017 considered eligible for chemoprevention (history of lobular carcinoma in situ, atypia, family history of breast/ovarian cancer, genetic mutation, or history of chest wall radiation) were retrospectively identified. Breast cancer risk factors were compared among those with and without chemoprevention use, and compliance was noted. RESULTS: Overall, 1506 women were identified, 24% with prior/current chemoprevention use. Women ≥ 50 years of age were more likely to use chemoprevention than women < 50 years of age (28% vs. 11%, p < 0.001). Chemoprevention use by risk factor ranged from 7 to 40%. Having multiple risk factors did not increase use. Significant variation by risk factor was present among women ≥ 50 years of age (p < 0.001), but not among women < 50 years of age (p = 0.1). Among women with a documented discussion regarding chemoprevention (575/1141), fear of adverse effects was the most common refusal reason (57/156; 36%). The majority of women (61%) who initiated chemoprevention completed 5 years. CONCLUSION: Chemoprevention use among women at increased risk for breast cancer remains low, with more frequent use among women ≥ 50 years of age. These data highlight the need for ongoing educational efforts and counseling, as the majority who begin therapy complete 5 years of use. Given the fear of adverse effects as well as low uptake, particularly among women < 50 years of age, alternative risk-reducing strategies are needed.

No survival improvement of contralateral prophylactic mastectomy among women with invasive lobular carcinoma.

BACKGROUND AND OBJECTIVE: The prognosis of contralateral prophylactic mastectomy (CPM) in women with breast cancer has been widely reported. Here, we evaluated the survival outcome among patients with invasive lobular carcinoma (ILC) to determine the potential benefit of CPM. METHODS: We used the Surveillance, Epidemiology, and End Results database to identify patients with ILC diagnosed between 1998 and 2010. Survival differences were compared between unilateral mastectomy and CPM. Propensity score matching and risk-stratified subgroup analyses were conducted to reduce selection bias. RESULTS: Among 10 226 patients with ILC, 21.8% women underwent CPM, and the rate of CPM nearly tripled over a 13-year period. Kaplan-Meier curves and hazard ratio (HR) of non-breast cancer-specific survival (non-BCSS) in multivariate analysis reflected a pre-existing selection bias in the present cohort. A Cox proportional hazard model confirmed that patients who received CPM had significantly better BCSS and overall survival (OS) in the prematching population (BCSS: HR = 0.90; OS: HR = 0.93). However, the survival improvement could not be achieved in the postmatching cohort. None of the defined subgroups had OS benefits when CPM was performed. CONCLUSIONS: CPM offers no survival advantage to patients with ILC. The role of CPM among ILC women should be further investigated by incorporating more objective factors.

Comparing Therapeutic versus Prophylactic Nipple-Sparing Mastectomy: Does Indication Inform Oncologic and Reconstructive Outcomes?

BACKGROUND: Initially performed only in prophylactic cases, indications for nipple-sparing mastectomy have expanded. Trends and surgical outcomes stratified by nipple-sparing mastectomy indication have not yet been fully examined. METHODS: Demographics and outcomes for all nipple-sparing mastectomies performed from 2006 to 2017 were compared by mastectomy indication. RESULTS: A total of 1212 nipple-sparing mastectomies were performed: 496 (40.9 percent) for therapeutic and 716 (59.1 percent) for prophylactic indications. Follow-up time was similar between both the therapeutic and prophylactic nipple-sparing mastectomy groups (47.35 versus 46.83 months, respectively; p = 0.7942). Therapeutic nipple-sparing mastectomies experienced significantly greater rates of major (p = 0.0165) and minor (p = 0.0421) infection, implant loss (p = 0.0098), reconstructive failure (p = 0.0058), and seroma (p = 0.0043). Rates of major (p = 0.4461) and minor (p = 0.2673) mastectomy flap necrosis and complete (p = 0.3445) and partial (p = 0.7120) nipple necrosis were equivalent. The overall rate of locoregional recurrence/occurrence per nipple-sparing mastectomy was 0.9 percent: 2.0 percent in therapeutic nipple-sparing mastectomies and 0.1 percent in prophylactic nipple-sparing mastectomies (p < 0.0001). CONCLUSIONS: Approximately 40 percent of nipple-sparing mastectomies are currently performed for therapeutic indications. Therapeutic nipple-sparing mastectomies had higher rates of infectious complications and reconstructive failure. Rates of locoregional cancer recurrence/occurrence are low, but occur significantly more often after therapeutic nipple-sparing mastectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Indications for Contralateral Prophylactic Mastectomy: A Consensus Statement Using Modified Delphi Methodology.

OBJECTIVE: To reach a consensus about contralateral prophylactic mastectomy in unilateral breast cancer. SUMMARY BACKGROUND DATA: There has been a substantial increase in the number of North American women with unilateral breast cancer undergoing a therapeutic mastectomy and a contralateral prophylactic mastectomy (CPM) either simultaneously or sequentially. The purpose of this project was to create a nationally endorsed consensus statement for CPM in women with unilateral breast cancer using modified Delphi consensus methodology. METHODS: A nationally representative expert panel of 19 general surgeons, 2 plastic surgeons, 2 medical oncologists, 2 radiation oncologists, and 1 psychologist was invited to participate in the generation of a consensus statement. Thirty-nine statements were created in 5 topic domains: predisposing risk factors for breast cancer, tumor factors, reconstruction/symmetry issues, patient factors, and miscellaneous factors. Panelists were asked to rate statements on a 7-point Likert scale. Two electronic rounds of iterative rating and feedback were anonymously completed, followed by an in-person meeting. Consensus was reached when there was at least 80% agreement. RESULTS: Our panelists did not recommend for average risk women with unilateral breast cancer. The panel recommended CPM for women with a unilateral breast cancer and previous Mantle field radiation or a BrCa1/2 gene mutation. The panel agreed that CPM could be considered by the surgeon on an individual basis for: women with unilateral breast cancer and a genetic mutation in the CHEK2/PTEN/p53/PALB2/CDH1 gene, and in women who may have significant difficulty achieving symmetry after unilateral mastectomy. CONCLUSION: Contralateral prophylactic mastectomy is rarely recommended for women with unilateral breast cancer.

Risk communication and decision-making in the prevention of invasive breast cancer.

Risk communication surrounding the prevention of invasive breast cancer entails not only understanding of the disease, risks and opportunities for intervention. But it also requires understanding and implementation of optimal strategies for communication with patients who are making these decisions. In this article, available evidence for the issues surrounding risk communication and decision making in the prevention of invasive breast cancer are reviewed and strategies for improvement are discussed.

Preventing invasive breast cancer using endocrine therapy.

Developments in breast cancer treatment have resulted in reduction in breast cancer mortality in the developed world. However incidence continues to rise and greater use of preventive interventions including the use of therapeutic agents is needed to control this burden. High quality evidence from 9 major trials involving more than 83000 participants shows that selective oestrogen receptor modulators (SERMs) reduce breast cancer incidence by 38%. Combined results from 2 large trials with 8424 participants show that aromatase inhibitors (AIs) reduce breast cancer incidence by 53%. These benefits are restricted to prevention of ER positive breast cancers. Restricting preventive therapy to high-risk women improves the benefit-harm balance and many guidelines now encourage healthcare professionals to discuss preventive therapy in these women. Further research is needed to improve our risk-prediction models for the identification of high risk women for preventive therapy with greater accuracy and to develop surrogate biomarkers of response. Long-term follow-up of the IBIS-I trial has provided valuable insights into the durability of benefits from preventive therapy, and underscores the need for such follow up to fully evaluate other agents. Full utilisation of preventive therapy also requires greater knowledge and awareness among both doctors and patients about benefits, harms and risk factors. Healthcare professionals should routinely discuss preventive therapy with women at high-risk of breast cancer.

Breast cancer prevention strategies in lobular carcinoma in situ: A decision analysis.

BACKGROUND: Women diagnosed with lobular carcinoma in situ (LCIS) have a 3-fold to 10-fold increased risk of developing invasive breast cancer. The objective of this study was to evaluate the life expectancy (LE) and differences in survival offered by active surveillance, risk-reducing chemoprevention, and bilateral prophylactic mastectomy among women with LCIS. METHODS: A Markov simulation model was constructed to determine average LE and quality-adjusted LE (QALE) gains for hypothetical cohorts of women diagnosed with LCIS at various ages under alternative risk-reduction strategies. Probabilities for invasive breast cancer, breast cancer-specific mortality, other-cause mortality and the effectiveness of preventive strategies were derived from published studies and from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. RESULTS: Assuming a breast cancer incidence from 1.02% to 1.37% per year under active surveillance, a woman aged 50 years diagnosed with LCIS would have a total LE of 32.78 years and would gain 0.13 years (1.6 months) in LE by adding chemoprevention and 0.25 years (3.0 months) in LE by adding bilateral prophylactic mastectomy. After quality adjustment, chemoprevention resulted in the greatest QALE for women ages 40 to 60 years at LCIS diagnosis, whereas surveillance remained the preferred strategy for optimizing QALE among women diagnosed at age 65 years and older. CONCLUSIONS: In this model, among women with a diagnosis of LCIS, breast cancer prevention strategies only modestly affected overall survival, whereas chemoprevention was modeled as the preferred management strategy for optimizing invasive disease-free survival while prolonging QALE form women younger than 65 years. Cancer 2017;123:2609-17. © 2017 American Cancer Society.

Use of immediate breast reconstruction and choice for contralateral prophylactic mastectomy.

BACKGROUND: Rates of contralateral prophylactic mastectomy (CPM) have been increasing nationally. The goal of this study was to evaluate recent trends in rates of CPM and immediate breast reconstruction (IBR). METHODS: After institutional review board approval, we evaluated all surgical procedures for women with newly diagnosed unilateral stages 0-III breast cancer from January 2009 to December 2014. Patients opting for therapeutic mastectomy were classified as either unilateral mastectomy or bilateral mastectomy, if CPM was performed, and according to whether or not they underwent IBR. Analysis was performed using trend tests for univariate associations and both binary and multinomial logistic regression for multivariate analysis. RESULTS: There were 3,195 women who underwent surgery for breast cancer--51% lumpectomy, 49% therapeutic mastectomy. Of the 1,571 patients undergoing therapeutic mastectomy, 829 (53%) underwent bilateral mastectomy. The rates of therapeutic mastectomy did not change over the study period (P = .92), but the use of IBR among patients undergoing therapeutic mastectomy increased from 37% in 2009 to 68% in 2014 (P < .0001). The use of bilateral mastectomy with IBR increased from 26% in 2009 to 46% in 2014 (P < .0001), whereas conversely the use of bilateral mastectomy without IBR decreased from 22% to 12% (P < .0001). IBR was associated with bilateral mastectomy; 69% of patients opting for IBR also underwent bilateral mastectomy compared with 38% choosing bilateral mastectomy in the group without IBR (adjusted odds ratio, 2.7; 95% CI, 2.1-3.5; P < .0001). CONCLUSION: Over recent years, rates of bilateral mastectomy have remained high. The use of IBR increased substantially for women undergoing therapeutic mastectomy and women undergoing IBR were significantly more likely to opt for bilateral mastectomy. The availability of IBR may influence patients' decisions to pursue bilateral mastectomy.

Is Excisional Biopsy and Chemoprevention Warranted in Patients With Atypical Lobular Hyperplasia on Core Biopsy?

The management of atypical lobular hyperplasia (ALH) on core biopsy remains controversial. The upstaging rates after surgical excision vary. We reviewed our upgrade rates and use of chemoprevention for ALH. Patients were identified through our pathology database for ALH from 2006 to 2013. Patients were included in the study that had a diagnosis only of ALH on core needle biopsy. Tumor and patient characteristics and final pathology were analyzed. ALH was identified in 56 patients since 2006. Sixteen patients met the inclusion criteria. All the patients underwent surgical excision. Final pathology of the excised specimens confirmed ALH in 62 per cent (n = 11). Two cases contained lobular carcinoma in situ. The upgrade rate on excisional biopsy was 18.75 per cent (n = 3) to invasive cancer. Chemopreventative treatment was taken by 44 per cent of the patients. After a mean follow-up of three years, none of the patients who received chemoprevention developed breast cancer. One patient who refused tamoxifen developed breast cancer. This is one of the few studies to examine the current treatment of ALH. We noted a significant upstaging rate after excision. We recommend women to undergo surgical excision. Patients should also consider chemoprevention to reduce their risk for developing breast cancer.

Contralateral Prophylactic Mastectomy: Challenging Considerations for the Surgeon.

The use of both bilateral prophylactic mastectomy and contralateral prophylactic mastectomy (CPM) has increased significantly during the last decade. Various risk models have been developed to identify patients at increased risk for breast cancer. The indications for bilateral prophylactic mastectomy for patients without a diagnosis of breast cancer include high risk from mutation in BRCA or other breast cancer predisposition gene, very strong family history with no identifiable mutation, and high risk based on breast histology. Additionally, the use of CPM has more than doubled in the last decade, and this increase is noted among all stages of breast cancer, even in patients with ductal carcinoma in situ (stage 0). The risk of contralateral breast cancer often is overestimated by both patients and physicians. Nevertheless, specific risk factors are associated with an increased risk of contralateral breast cancer, including BRCA or other genetic mutation, young age at diagnosis, lobular histology, family history, and prior chest wall irradiation. Although CPM reduces the incidence of contralateral breast cancer, the effect on disease-free survival and, more importantly, overall survival is questionable and underscored by the fact that the reason most patients choose CPM is to achieve "peace of mind." Newer and effective reconstructive options have made the procedure more attractive. This panel addresses the indications and rationale for bilateral prophylactic mastectomy and CPM, the decision-making process by patients, and ethical considerations. Changes in the physician-patient relationship during the past few decades have altered the approach, and ethical considerations are paramount in addressing these issues.

Variation in Contralateral Prophylactic Mastectomy Rates According to Racial Groups in Young Women with Breast Cancer, 1998 to 2011: A Report from the National Cancer Data Base.

BACKGROUND: The rate of contralateral prophylactic mastectomy (CPM) for unilateral breast cancer has increased over the past decade, particularly for young women. This study investigates the impact of race and socioeconomic status (SES) on use of CPM. STUDY DESIGN: Using the National Cancer Data Base (NCDB), we selected 1,781,409 stage 0 to II unilateral breast cancer patients between 1998 and 2011. Trends in use of CPM by race and SES were analyzed using chi-square tests and logistic regression models. RESULTS: For women of all ages, rates of CPM increased, from 1.9% in 1998 to 10.2% in 2011 (p < 0.001), with higher rates in women ≤45 years old, rising from 3.7% in 1998 to 26.2% in 2011 (p < 0.001). Among young women, white women had the greatest increase in CPM from 4.3% in 1998 to 30.2% in 2011 (p < 0.001). In 2011, CPM rates were 30.2% for white, 18.5% for Hispanic, 16.5% for black, and 15.2% for Asian patients (p < 0.001). The gap in CPM use between white and minority patients persisted in every SES classification, geographic region, and facility type. On multivariate analysis, minority women were 50% less likely to undergo CPM than white women were. CONCLUSIONS: Young, white, breast cancer patients are twice as likely to undergo CPM compared with women in other racial groups, even after accounting for pathologic, patient, and facility factors. Variations in shared decision-making processes between women of different backgrounds may contribute to these trends, supporting the need for future studies investigating decision-making processes and decisional aids.

Variation in Breast Cancer-Risk Factor Associations by Method of Detection: Results From a Series of Case-Control Studies.

Concerns about breast cancer overdiagnosis have increased the need to understand how cancers detected through screening mammography differ from those first detected by a woman or her clinician. We investigated risk factor associations for invasive breast cancer by method of detection within a series of case-control studies (1992-2007) carried out in Wisconsin, Massachusetts, and New Hampshire (n=15,648 invasive breast cancer patients and 17,602 controls aged 40-79 years). Approximately half of case women reported that their cancer had been detected by mammographic screening and half that they or their clinician had detected it. In polytomous logistic regression models, parity and age at first birth were more strongly associated with risk of mammography-detected breast cancer than with risk of woman/clinician-detected breast cancer (P≤0.01; adjusted for mammography utilization). Among postmenopausal women, estrogen-progestin hormone use was predominantly associated with risk of woman/clinician-detected breast cancer (odds ratio (OR)=1.49, 95% confidence interval (CI): 1.29, 1.72), whereas obesity was predominantly associated with risk of mammography-detected breast cancer (OR=1.72, 95% CI: 1.54, 1.92). Among regularly screened premenopausal women, obesity was not associated with increased risk of mammography-detected breast cancer (OR=0.99, 95% CI: 0.83, 1.18), but it was associated with reduced risk of woman/clinician-detected breast cancer (OR=0.53, 95% CI: 0.43, 0.64). These findings indicate important differences in breast cancer risk factors according to method of detection.

Sentinel lymph node biopsy during prophylactic mastectomy: is there a role?

PURPOSE: We investigated rates of occult malignancy in the breast and sentinel lymph nodes (SLNs) in patients undergoing prophylactic mastectomy (PM) and whether routine sentinel lymph node biopsy (SLNB) is justified. METHODS: A retrospective review of our database identified patients undergoing PMs with SLNB. Descriptive statistics were utilized for data summary. A P value of <0.05 was considered significant. RESULTS: There were 384 patients during the study period who underwent 467 PMs. Of the 467 PMs, 15 (3.2%) cancers were found on final pathology. All 6 of the invasive cancers identified were T1. A total of 682 SLNs were taken for an average of 1.46 SLNs per PM. There were 5 positive SLNs (1.1%). All were in patients undergoing contralateral PM for either history of breast cancer or new diagnosis of breast cancer. Only one patient with a positive SLN was found to have an occult breast malignancy in the PM specimen. CONCLUSION: In 467 PMs performed, 15 (3.2%) occult malignancies were found in the breast and 5 (1.1%) positive SLNs were found. Based on these results, the routine use of SLNB at the time of PM is unnecessary and does not warrant the morbidity associated with this procedure.

Contralateral prophylactic mastectomy in an Asian population: a single institution review.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) removes the non-diseased breast in women who have unilateral breast cancer. This reduces the incidence of contralateral breast cancer, and potentially improves survival in high risk patients. Such surgical risk-reduction strategy is increasingly being adopted in the United States, despite a decreasing incidence of contralateral breast cancer. The use of CPM in an Asian population is yet unknown. We present the first Asian report on CPM rates and trends in Singapore, the country with the highest incidence of breast cancer in Asia. METHODS: A retrospective review of all patients who had breast cancer surgery from 2001 to 2010 at the largest healthcare system in Singapore was performed. Patient demographics and tumour characteristics were analysed with regards to type of surgery performed. Factors associated with CPM were identified. RESULTS: From 2001 to 2010, a total of 5130 patients underwent oncological breast surgery. A decreasing trend of mastectomies (82.7%-70.8%), an upward trend of breast conserving surgery (BCS) (17.3%-29.2%) and an increasing trend in CPM (0.46%-1.25%) is observed. Patients who opted for CPM are likely to be younger (48.4 ± 9.4 years), married (60%), parous (56.7%), with no family history of breast/ovarian cancer (66.7%), and diagnosed at an earlier stage. The rate of synchronous occult breast malignancy was found to be 10% (n = 30), and these were in patients who were of a low cancer-risk profile. CONCLUSIONS: This retrospective study reflects an increasing incidence of breast cancer in Singapore, with a decrease in mastectomies, and an increase in BCS and CPM rates, similar to Western data. Similar to Western populations, the Asian woman who opts for CPM is likely to be young and have an earlier stage of breast cancer. In contrast, the Asian woman is likely to have no family history of breast or ovarian cancers. Commonly cited reasons for increased CPM rates such as the increased availability of genetic counselling and pre-operative MRI evaluation, along with wide use of reconstruction, do not feature as dominant factors in our population, suggesting that the Asian patients may have different considerations when electing for CPM.

MicroRNA-30a suppresses breast tumor growth and metastasis by targeting metadherin.

Accumulating data have shown the involvement of microRNAs in cancerous processes as either oncogenes or tumor suppressor genes. Here, we established miR-30a as a tumor suppressor gene in breast cancer development and metastasis. Ectopic expression of miR-30a in breast cancer cell lines resulted in the suppression of cell growth and metastasis in vitro. Consistently, the xenograft mouse model also unveiled the suppressive effects of miR-30a on tumor growth and distal pulmonary metastasis. With dual luciferase reporter assay, we revealed that miR-30a could bind to the 3'-untranslated region of metadherin (MTDH) gene, thus exerting inhibitory effect on MTDH. Furthermore, we demonstrated that silence of MTDH could recapitulate the effects of miR-30a overexpression, while overexpression of MTDH could partially abrogate miR-30a-mediated suppression. Of significance, expression level of miR-30a was found to be significantly lower in primary breast cancer tissues than in the paired normal tissues. Further evaluation verified that miR-30a was negatively correlated with the extent of lymph node and lung metastasis in patients with breast cancer. Taken together, our findings indicated miR-30a inhibits breast cancer proliferation and metastasis by directly targeting MTDH, and miR-30a can serve as a prognostic marker for breast cancer. Manipulation of miR-30a may provide a promising therapeutic strategy for breast cancer treatment.

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial.

BACKGROUND: Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease. METHODS: Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40-70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specific criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratified by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319. FINDINGS: 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5·0 years (IQR 3·0-7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0·47, 95% CI 0·32-0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836). INTERPRETATION: Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer. FUNDING: Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca.