Clinical and experimental effects of neoadjuvant treatment of endometrial cancer patients with non-steroidal aromatase inhibitors: letrozole (femara, n=10, 2.5 mg/day, 14 days), anastrozole (arimidex, n=15,1 mg/day, 28 days) and exemestane (aromazine, n=13, 25 mg/day, 14 days) were compared. Administration of anastrozole was mostly frequently followed by pain relief in the lower abdomen and/or decreased rates of uterine discharge. Endometrial wall thickness (M-echo signal) decreased significantly in 60% of patients receiving anastrozole, exemestane - 58.3% and letrozole - 40%. Substantial drop in intratumoral aromatase and blood estradiol levels occurred more frequently after anastrozole and letrozole while progesterone receptor levels in tumor were markedly lower after exemestane administration. Assay of blood LH (except letrozole), FSH and cholesterol appeared to be of less relevance. On the contrary, significance of assessment of marker Ki-67 expression, which, in the case of anastrozole, dropped in 6 out of 12 patients after a 28-day course, could hardly be underestimated.

PURPOSE: To evaluate potential detrimental effects of exemestane on bone and lipid metabolism. PATIENTS AND METHODS: Postmenopausal women with early breast cancer were randomly assigned to exemestane 25 mg daily or placebo for 2 years in a double-blind setting. Primary objective was to evaluate the effect of exemestane on bone mineral density. Secondary objectives were effects on bone biomarkers, plasma lipids, coagulation factors, and homocysteine. Planned size was 128 patients. RESULTS: One hundred forty-seven patients were enrolled. All patients completed their 24-month visit except for those discontinuing treatment at an earlier stage. The mean annual rate of bone mineral density loss was 2.17% v 1.84% in the lumbar spine (P =.568) and 2.72% v 1.48% in the femoral neck (P =.024) in the exemestane and placebo arm, respectively. The mean change in T-score after 2 years was -0.21 for exemestane and -0.11 on placebo in the hip, and -0.30 and -0.21, respectively, in the lumbar spine. Exemestane significantly increased serum level and urinary excretion of bone resorption, but also bone formation markers. Except for a modest reduction in high-density lipoprotein cholesterol (P <.001) and apolipoprotein A1 (P =.004), exemestane had no major effect on lipid profile, homocysteine levels, or coagulation parameters. CONCLUSION: Exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss. Except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were recorded. Bone mineral density should be assessed according to the US Preventive Services Task Force guidelines.

INTRODUCTION: Long-term endocrine therapy for breast cancer may have clinical implications as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease. In this study, a companion sub-protocol to the TEAM (Tamoxifen and Exemestane Adjuvant Multicenter) International trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal women with early breast cancer in the adjuvant setting to that of tamoxifen. PATIENTS AND METHODS: In this open-label, randomized, parallel group study, 176 postmenopausal patients with estrogen and/or progesterone receptor positive early breast cancer were randomized to either adjuvant exemestane (25 mg/day; n = 90) or tamoxifen (20 mg/day; n = 86). Assessments of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and serum triglycerides (TRG) were performed at baseline and every 3 months for the first 12 months. RESULTS: Serum triglyceride levels were consistently increased above baseline throughout the study in the tamoxifen arm, while there was a trend towards reduction in the exemestane arm. There was also an overall trend for tamoxifen to decrease the levels of LDL throughout the study period. Exemestane did not demonstrate any other significant change in HDL levels; however, there was a consistent trend for a reduction in total cholesterol in both treatment arms. The atherogenic risk determined by the TC:HDL ratio remained stable in both arms throughout the treatment period. CONCLUSIONS: Exemestane appears to have a neutral effect on total cholesterol and HDL levels. Unlike tamoxifen's positive effect on LDL levels, exemestane does not significantly alter LDL levels. Tamoxifen on the other hand increases triglyceride levels, while exemestane results in a beneficial reduction in TRG levels. These data offer additional information with regard to the safety and tolerability of exemestane in postmenopausal breast cancer patients and support further investigation of its potential usefulness in the adjuvant setting.

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer.

OBJECTIVE: To evaluate the pharmacokinetic, pharmacodynamic, and safety profiles of the aromatase inhibitor anastrozole in healthy, premenopausal women. DESIGN: Phase I, single-center study. SETTING: Infertility clinic. PATIENT(S): Twenty-six women with regular ovulatory cycles: 20 received either a single dose of 5 mg, 10 mg, 15 mg, or 20 mg anastrozole, or remained untreated; 6 received five daily doses of 10 mg or 15 mg anastrozole. INTERVENTION(S): Anastrozole was administered on cycle day 2 for the single-dose groups and on days 2-6 for the multiple-dose groups. Ultrasound follicular development and endometrial biopsies were performed. Safety was determined from adverse event reports and laboratory parameters. MAIN OUTCOME MEASURE(S): Pharmacokinetics, pharmacodynamics, and safety. RESULT(S): The pharmacokinetics of anastrozole were linear, predictable, and consistent with previously published data in healthy volunteers. In the single-dose groups, E2 levels reached their nadir 3-6 hours after administration, decreasing by an average of 39% from baseline. Follicle-stimulating hormone levels rose by 13%, 52%, 49%, and 75% in the 5-mg, 10-mg, 15-mg, and 20-mg groups, respectively, at approximately 24 hours after dosing. Most subjects recruited just one mature follicle, with no apparent effect on endometrial maturation. No safety concerns were noted. CONCLUSION(S): Anastrozole was well tolerated and suppressed E2 levels, with a resultant increase in FSH.

Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues.

Adjuvant tamoxifen is still considered standard care for postmenopausal women with early stage hormone receptor-positive breast cancer. However, efficacy and safety of tamoxifen are limited by its partially estrogenic properties. Aromatase inhibitors have proven highly effective in advanced breast cancer and are currently being investigated in the adjuvant setting, either as an alternative to or in sequence with tamoxifen, or as extended adjuvant therapy following tamoxifen. Results of several adjuvant aromatase inhibitor trials have been published and strongly indicate that efficacy may be increased compared with tamoxifen alone. This review will examine the published data, discuss ongoing trials, and address the question of how to best integrate the aromatase inhibitors into adjuvant treatment.

The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor-positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localised breast cancer. After a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with tamoxifen, hazard ratio 0.87, 95% CI 0.78-0.97, p=0.01) and time-to-recurrence (402 vs 498, 0.79, 0.70-0.90, p=0.0005), and significantly reduced distant metastases (324 vs 375, 0.86, 0.74-0.99, p=0.04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0.01). Almost all patients have completed their scheduled treatment, and fewer withdrawals occurred with anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures were increased. Anastrozole should be the preferred initial treatment for postmenopausal women with localised hormone-receptor-positive breast cancer.

Earlier detection of invasive and noninvasive breast cancer and more effective treatments have led to both an improved prognosis for women with breast cancer and an increasing number of long-term survivors. However, such advances present various physical and emotional health challenges to patients facing breast cancer and its aftermath. Thus, understanding of the specific medical and psychosocial problems associated with survivorship is paramount in primary care.

AIMS: Although the third-generation aromatase inhibitors are generally well tolerated, side-effects still occur in up to 40% of women. As more women are taking these drugs for longer, the issue as to which version is better tolerated is now a significant patient concern. This study aimed to assess whether tolerance for either letrozole or anastrozole can differ for each individual in terms of early quality of life (QoL), whether patients welcome being given a preference and whether this correlated with formal toxicity scoring. MATERIALS AND METHODS: A single-blind, crossover trial, with 72 women with breast cancer who had experienced tamoxifen failure. Randomised to either letrozole 2.5 mg or anastrozole 1 mg, for 4 weeks, 1 week off, then crossover for 4 weeks. RESULTS: Patients were confidently able to choose which drug suited them best (letrozole 68%, anastrozole 32%; P < 0.01). Fewer patients, when taking letrozole, experienced adverse events than when taking anastrozole (43% vs 65%; P = 0.0028). QoL was better when patients were taking letrozole than when they took anastrozole (P = 0.02). CONCLUSIONS: As toxicity and QoL strongly correlated with patient preference for either drug, albeit with a tendency towards letrozole, this suggests that patient preference is now a legitimate and useful end point for future crossover studies. In routine practice, women would warmly welcome extra involvement in the decision-making process via a crossover manoeuvre if side-effects develop, whichever aromatase inhibitor is prescribed initially.

Breast cancer is now the most common malignancy diagnosed in women. Growth factor and estrogen receptors elicit tight regulation of breast tumor progression. Estrogen receptors occur in about two-thirds of breast tumors, and endocrine therapy targeted to these receptors is effective in a large proportion of tumors that express both estrogen and progesterone receptors. However, after an initial period of response to hormonal therapy, such as tamoxifen, most tumors develop resistance leading to disease relapse. Emerging data suggest that previously unsuspected interactions between growth factor and estrogen signaling pathways contribute to growth promotion in breast cancer. Targeting different components of this signaling axis may allow development of more effective and less toxic anti-hormone treatments for breast cancer. In recent clinical studies, anastrozole, letrozole and exemestane, inhibitors of the estrogen synthase, aromatase, have shown advantages over tamoxifen as treatment for advanced disease. Fulvestrant is a new type of estrogen receptor antagonist that down-regulates cellular levels of estrogen receptor and has no agonist activity. Due to its unique mode of action, fulvestrant may be an ideal candidate for combination treatment with inhibitors targeted to growth factor receptor signaling pathways. New understanding of estrogen receptor genes, gene transcripts and variants, post-translational modifications of receptor protein products and interactions with other signaling networks in tumor cells are leading us to unique targeted approaches in the hormonal therapy of breast cancer.