Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women

Tamoxifen improves outcome in women with breast cancer and reduces the incidence of estrogen receptor-positive (ER+) breast tumors in prevention trials. Tamoxifen use is associated with an increased risk of potentially serious adverse events, principally endometrial cancer and venous thromboembolic events and, therefore, detailed knowledge of the effects of tamoxifen is important. With more cases of breast cancer being found as the follow-up time increases, it is now possible to perform more detailed analysis of the Italian Randomized Trial of Tamoxifen. Women with hysterectomy (N = 5408) were randomly assigned to receive 20 mg tamoxifen per day (N = 2700) or placebo (N = 2708). After a median of 81.2 months of follow-up, 79 case subjects (34 in the tamoxifen arm and 45 in the placebo arm) were diagnosed with breast cancer. We were able to identify a group of women at increased risk of ER+ breast cancers (high-risk group) on the basis of baseline as well as reproductive and hormonal characteristics (height, age at menarche, parity, age at first birth, and oophorectomy). Tamoxifen administered to women in the high-risk group showed statistically significantly reduced incidence of breast cancer (tamoxifen, 3 and placebo, 15; P =.003), but no such effect was seen in the low-risk group (tamoxifen, 31 and placebo, 30; P =.89). The positive effect of tamoxifen on breast cancer among high-risk women is most marked for ER+ tumors (tamoxifen, 1 and placebo, 11; P =.002). Chemoprevention of breast cancer with tamoxifen appears to be effective in women at high risk of ER+ tumors but not among women at low risk, who may well be protected naturally by late age at menarche or early first pregnancy, or artificially by removal of the ovaries. Tamoxifen could be offered as a preventive agent to women identified at high-risk of breast cancer because of hormone-related risk factors. Such a strategy would greatly reduce the numbers of women who would need to take tamoxifen to obtain the same absolute reduction in breast cancer. These findings are exploratory and need to be confirmed in other randomized trials.     

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.     

Preventing breast cancer in high-risk women, 2008

Several large, prospective trials have evaluated tamoxifen compared with placebo for breast cancer risk reduction in women at increased risk for breast cancer. Analysis of the large, prospective breast cancer risk-reduction trials that used tamoxifen estimated that tamoxifen decreased breast cancer incidence by 38% on average and estrogen receptor-positive tumors by 48%. Tamoxifen is known to have several serious side effects, including uterine malignancy, thromboembolic events, cataracts, and menopausal symptoms, that have limited its usefulness in the risk-reduction setting. Raloxifene (Evista) is a benzothiophene selective estrogen-receptor modulator that has antiestrogenic effects on breast and endometrial tissue as well as estrogenic effects that are similar to but distinct from tamoxifen. Among postmenopausal women who are at increased risk for breast cancer, raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer but appears to be less effective than tamoxifen in reducing the risk of in situ breast cancer. Raloxifene causes less benign and malignant uterine changes and fewer thromboembolic events than tamoxifen. Symptomatic side effects are comparable for the two drugs. Raloxifene is more appropriate than tamoxifen for reduction of breast cancer risk among postmenopausal women at increased risk for breast cancer.     

Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer

The records of 2,673 patients randomized according to seven consecutive Eastern Cooperative Oncology Group (ECOG) studies of adjuvant therapy for breast cancer were reviewed for the occurrence of vascular complications. All protocols opened and closed between June 1977 and July 1987. The objectives of the present study were (1) to compare the frequency of vascular complications among patients who received adjuvant therapy for breast cancer with patients on observation, and (2) to estimate the contribution of chemotherapy and hormonal therapy to the occurrence of venous and arterial thrombi. The frequency of thrombosis, both venous and arterial combined, was 5.4% among patients who received adjuvant therapy and was 1.6% among patients on observation (P = .0002). Premenopausal patients who received chemotherapy and tamoxifen had significantly more venous complications than those who received chemotherapy without tamoxifen (2.8% v 0.8%, P = .03). Postmenopausal patients who received tamoxifen and chemotherapy had significantly more venous thrombi than those who received tamoxifen alone (8.0% v 2.3%, P = .03) or those who were observed (8.0% v 0.4%, P less than .0001). Premenopausal patients who received tamoxifen and chemotherapy had a 1.6% frequency of arterial thrombosis, significantly more than patients who received chemotherapy alone (1.6% v 0.0%, P = .004). The frequency of arterial thrombosis among postmenopausal patients was not significantly correlated with adjuvant therapy. In conclusion, patients who received adjuvant therapy for breast cancer had a 5.4% frequency of thromboembolic complications, significantly more than those who were observed. The combination of chemotherapy and tamoxifen was associated with more venous and arterial thromboembolic complications than chemotherapy alone in premenopausal patients and with more venous thrombi than tamoxifen alone among postmenopausal patients.     

Should women be advised to take prophylactic endocrine treatment outside of a clinical trial setting?

Epidemiological, experimental and clinical data strongly support the possibility that breast cancer can be prevented by using anti-estrogenic interventions in healthy women. Four trials involving over 25,000 women have so far been reported using tamoxifen 20 mg/day or placebo in healthy women to chemoprevent breast cancer, and several trials utilizing raloxifene or aromatase inhibitors are underway. Interim analyses of the Royal Marsden tamoxifen trial and the Italian national trial showed no effect on the early incidence of breast cancer. The NSABP-P1 showed a 49% reduction in early incidence of breast cancer. This was associated with a reduction in osteoporotic fractures but increases in the risks of endometrial cancer, cataract and thromboembolism. The IBIS trial showed a 32% reduction with a two-fold increase in endometrial cancer and in thromboembolic events. Mortality rates of breast cancer in women receiving tamoxifen prophylactically should be monitored and further follow-up of these trials is needed to determine whether tamoxifen provides an overall health benefit or increase specific or overall survival of breast cancer. High-risk women should not be advised to take anti-estrogens outside of a clinical trial setting.     

Tamoxifen in ductal carcinoma in situ

The widespread adoption of screening mammography has resulted in an increased incidence of ductal carcinoma in situ (DCIS), which now accounts for 20% to 30% of new breast cancer diagnoses. Despite treatment with combined lumpectomy and radiation therapy, up to 15% of women will experience an ipsilateral breast recurrence, with 50% of these recurrences containing invasive disease. There is also a 6% incidence of contralateral breast cancers in women treated for DCIS. The recognition that adjuvant tamoxifen reduces local, regional, and distant disease in women diagnosed with invasive breast cancer led to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 study, which randomized more than 1,800 women undergoing breast-sparing surgery and radiation for DCIS to adjuvant tamoxifen versus placebo for 5 years. At 7 years of follow-up, there was a statistically significant 27% reduction in the annual incidence rate of all breast cancer-related events for those women receiving tamoxifen, including a 48% reduction in invasive breast cancer. The benefit attributable to tamoxifen was confined to those tumors that were estrogen receptor (ER)-positive. However, adverse events, including endometrial cancer, thromboembolic events, and cataracts, are more common in older women. Tamoxifen should be considered as an adjunct to treatment for women undergoing breast-conserving surgery for ER-positive DCIS.     

The ATAC trial: the vanguard trial for use of aromatase inhibitors in early breast cancer

The Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial was the first trial to explore the use of aromatase inhibitors in post-menopausal women with early breast cancer and is the largest published cancer treatment trial in breast cancer. The main results have been published at 33-, 47- and 68-month median follow-up, and further analyses are planned for the end of 2007 and in 2010. This trial demonstrated that 5 years of treatment with anastrozole was generally better tolerated than 5 years of treatment with tamoxifen, and led to lower recurrence rates, especially in receptor-positive women (26% reduction). The side-effect profile was different than that for tamoxifen, with fewer hot flushes, gynecologic symptoms, endometrial cancers, strokes and thromboembolic events; however, an increased incidence of fractures, joint symptoms and carpal tunnel syndrome was observed. Future analyses will determine whether benefits and fracture rates persist after stopping treatment, and the extent to which currently marginal benefits on late end points, such as distant recurrence and death after recurrence, are sustained or improved.     

The ATAC trial: the vanguard trial for use of aromatase inhibitors in early breast cancer

The Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial was the first trial to explore the use of aromatase inhibitors in post-menopausal women with early breast cancer and is the largest published cancer treatment trial in breast cancer. The main results have been published at 33-, 47- and 68-month median follow-up, and further analyses are planned for the end of 2007 and in 2010. This trial demonstrated that 5 years of treatment with anastrozole was generally better tolerated than 5 years of treatment with tamoxifen, and led to lower recurrence rates, especially in receptor-positive women (26% reduction). The side-effect profile was different than that for tamoxifen, with fewer hot flushes, gynecologic symptoms, endometrial cancers, strokes and thromboembolic events; however, an increased incidence of fractures, joint symptoms and carpal tunnel syndrome was observed. Future analyses will determine whether benefits and fracture rates persist after stopping treatment, and the extent to which currently marginal benefits on late end points, such as distant recurrence and death after recurrence, are sustained or improved.     

A brief review of the current breast cancer prevention trials and proposals for future trials

The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed of which three have reported efficacy results. A fifth trial using raloxifene has also been published. The largest tamoxifen trial shows approximately a 50% reduction in breast cancer incidence in the short term, but the two smaller trials have not found any incidence reduction. Greater agreement exists for side-effects - thromboembolic disease and endometrial cancers are raised about 2 to 3-fold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 42% reduction in short-term incidence. Several important questions remain about the clinical implication of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow-up of these trials is crucial for resolving these issues.     

The Royal Marsden Hospital pilot tamoxifen chemoprevention trial

A pilot randomised placebo controlled trial using tamoxifen in healthy women at increased risk of developing breast cancer, has been undertaken in order to evaluate the problems of accrual, acute symptomatic toxicity, compliance, and safety as a basis for subsequent large national multicentre trials designed to test whether tamoxifen can chemoprevent breast cancer.From October 1986 until June 1993, 2012 healthy women with an increased risk of developing breast cancer, usually because of a strong family history, were randomly allocated to receive tamoxifen 20 mgs/day or placebo for up to 8 years if possible.Accrual remained high in spite of extensive informed consent regarding potential risk. Acute symptomatic toxicity was low for participants on tamoxifen or placebo and compliance remained correspondingly high with a predicted 77% of women on tamoxifen and 82% of women on placebo continuing medication at 5 years. There was a significant increase in hot flushes (34% versus 20%) mostly in premenopausal women (p < 0.005), vaginal discharge (16% versus 4%, p < 0.005), and menstrual irregularities (14% versus 9%, p < 0.005). The requirements for hormone replacement therapy for women on tamoxifen or placebo were the same.Safety monitoring indicates no adverse anti oestrogenic effects of tamoxifen. There was no obvious effect of tamoxifen on bone mineral densities (single photon radial absorption). The fibrinogen and antithrombin III were both lowered, resulting in no observed detrimental effect on the ratio of these clotting factors. There was a significant reduction in the serum cholesterol maintained out to 5 years. Annual pelvic assessment using transvaginal ultrasound indicates an increased incidence of uterine fibromata and benign ovarian cysts. These results have encouraged the commencement of the NSABP national trial in the USA, and the subsequent start of national trials in Italy and the UK, which together should provide sufficient evidence to evaluate the efficacy of tamoxifen for prevention of breast cancer.     

Acute bilateral pulmonary emboli occurring while on adjuvant aromatase inhibitor therapy with anastrozole: case report and review of the literature

Hormonal therapy is the mainstay of adjuvant treatment for women with early-stage estrogen receptor-positive breast cancer. Recently, the aromatase inhibitors have moved to the forefront of adjuvant hormonal therapy, however, the adverse effects of these agents are not yet fully understood. It is generally accepted that tamoxifen, but not the aromatase inhibitors, is associated with an increased risk of thrombosis in women with breast cancer. Studies comparing aromatase inhibitors to tamoxifen in the adjuvant setting have reported a lower rate of venous thromboembolism with the aromatase inhibitors, yet the incidence of venous thromboembolism with these new agents is higher than that expected in the general population. Here we report a case of acute bilateral pulmonary emboli occurring while on adjuvant aromatase inhibitor therapy with anastrozole, and review the literature on the incidence of venous thromboembolism during the use of aromatase inhibitors in the adjuvant setting.     

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.     

Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer.

BACKGROUND: In response to findings from the Breast Cancer Prevention Trial that tamoxifen treatment produced a 49% reduction in the risk of invasive breast cancer in a population of women at elevated risk, the National Cancer Institute sponsored a workshop on July 7 and 8, 1998, to develop information to assist in counseling and in weighing the risks and benefits of tamoxifen. Our study was undertaken to develop tools to identify women for whom the benefits outweigh the risks. METHODS: Information was reviewed on the incidence of invasive breast cancer and of in situ lesions, as well as on several other health outcomes, in the absence of tamoxifen treatment. Data on the effects of tamoxifen on these outcomes were also reviewed, and methods were developed to compare the risks and benefits of tamoxifen. RESULTS: The risks and benefits of tamoxifen depend on age and race, as well as on a woman's specific risk factors for breast cancer. In particular, the absolute risks from tamoxifen of endometrial cancer, stroke, pulmonary embolism, and deep vein thrombosis increase with age, and these absolute risks differ between white and black women, as does the protective effect of tamoxifen on fractures. Tables and aids are developed to describe the risks and benefits of tamoxifen and to identify classes of women for whom the benefits outweigh the risks. CONCLUSIONS: Tamoxifen is most beneficial for younger women with an elevated risk of breast cancer. The quantitative analyses presented can assist health care providers and women in weighing the risks and benefits of tamoxifen for reducing breast cancer risk.     

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.     

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.     

Adjuvant tamoxifen in breast-cancer-treatment in postmenopausal women - occurrence of thromboembolic complications

Of 441 postmenopausal breast cancer patients who received adjuvant tamoxifen, 19 had thromboembolic accidents (4.3%). All were in remission when thrombosis occurred. One patient died of bilateral pulmonary embolism. In the other cases, thromboembolic disorders were found to be reversible after the withdrawal of tamoxifen and anticoagulant treatment. Some patients had a history of vascular disorders, and others required prolonged bed rest which may have contributed as an aggravating circumstance to thrombotic events. Our study suggests that thromboembolic risk factors as well as potential vascular disorders induced by aggravating conditions have to be carefully examined in postmenopausal patients treated by adjuvant tamoxifen therapy. This is especially true in women with lobular breast cancer and aged more than 60 years.     

Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial

BackgroundAdjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial.Patients and methodsPremenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years.ResultsIn the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients <40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40–49 years of age or ?50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time.ConclusionIn this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women <40 years of age. The effect of tamoxifen was not significantly dependent on time.     

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial: an update

Until recently, tamoxifen was the only adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early-stage breast cancer. However, the first efficacy update from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial has introduced a choice of adjuvant therapy in this setting. After a median follow-up of 47 months, these data indicated that anastrozole continued to show superior efficacy compared with tamoxifen, including significantly greater disease-free survival, a longer median time to recurrence, and a reduced incidence of contralateral breast cancer. Anastrozole also exhibited a number of important tolerability benefits compared with tamoxifen, including reduced incidences of thromboembolic events, vaginal bleeding, and endometrial cancer. Additional ATAC subprotocols included the examination of bone mineral density and its associated sequelae, endometrial abnormalities, and quality of life. The results of these studies support the primary conclusions of the main efficacy and safety analyses: the efficacy benefits of anastrozole were not at the expense of quality of life, anastrozole was associated with reduced endometrial stimulation compared with tamoxifen, and only patients receiving tamoxifen had endometrial atypical hyperplasia. Anastrozole was associated with a modest loss of bone mineral density and an initial increase of fractures compared with tamoxifen. However, the fracture rate with anastrozole stabilizes after 2 years, and indirect comparison suggests that any increased fracture risk with anastrozole is modest. This review concludes that, based on the overall risk-benefit profile from the ATAC study, anastrozole is a rational alternative to tamoxifen for the adjuvant treatment of women with hormone-sensitive early-stage breast cancer.     

Acute abdomen during adjuvant chemotherapy: superior mesenteric artery thrombosis associated with CMF chemotherapy

We report a case of superior mesenteric artery thrombosis in a 57–year-old woman undergoing chemotherapy for T₁N₁M₀ breast cancer. Although cancer itself is associated with an increased risk of thrombotic events, treatment with chemotherapy and/or tamoxifen in breast cancer patients increases this risk. Most cases reported are of venous thromboembolism; arterial events are rare.     

Future possibilities in the prevention of breast cancer: Breast cancer prevention trials

The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been reported. The largest tamoxifen trial showed approximately 50% reduction in breast cancer incidence in the short term, but the two smaller trials did not find any reduction. Greater agreement exists for side effects; incidences of thromboembolic disease and endometrial cancers are raised approximately threefold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 40% reduction in short-term incidence. Several important questions remain regarding the clinical implications of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow up of these trials is crucial for resolving these issues.