Treatment Of Postmenopausal Breast Cancer Research Articles

Role of fulvestrant in the management of postmenopausal breast cancer

Fulvestrant is a form of endocrine therapy used in the treatment of postmenopausal breast cancer. It has a unique mechanism of action in that it causes the degradation of estrogen receptor and therefore has been labeled a selective estrogen receptor downregulator. Unlike the selective estrogen receptor modulator tamoxifen, it has no agonistic properties and is therefore a pure anti-estrogen. Given its low level of bioavailability and presystemic metabolism, it has been formulated as an intramuscular injection. A number of dosing regimens have been utilized – these include a dose of 250 mg monthly (‘approved dose’), an initial 500 mg followed by 250 mg on days 14 and 28, and thereafter 250 mg every 28 days (‘loading dose’), or 500 mg on days 0, 14 and 28, and thereafter every 28 days (‘high dose’). This article will review its unique mode of action and preclinical data, as well as clinical data for different dosing regimens and data for its combination with aromatase inhibitors. Fulvestrant is a well-tolerated drug and its toxicities will also be reviewed. The optimal position of fulvestrant in sequential endocrine therapy has yet to be defined.

Sushi domain containing 3 (SUSD3) and its role in breast cancer cell morphology, migration, and adhesion

ObjectiveAromatase inhibitors (AIs) have become the mainstay of the endocrine treatment of postmenopausal breast cancer and we have identified SUSD3 to be down-regulated in AI non-responsive patients. We previously demonstrated a direct regulatory role of ERα in SUSD3 expression with localization of SUSD3 to the outer cellular membrane. We hypothesized a possible role of SUSD3 in breast cancer cell-to-cell adhesion and/or migration.DesignBasic science research.Materials and MethodsMCF7 breast cancer cells were transfected with siRNA targeting SUSD3 or a control siRNA. Morphological changes were documented by phase contrast microscopy 48 and 72 hours post-transfection. Western blot analyses for focal adhesion kinase (FAK), Src, and phosphorylated paxillin (p-Pax) were performed after 72 hr of siRNA transfection. Wound healing, dispase, and aggregation assays were performed after 72hr siRNA transfections and results were documented by phase contrast microscopy.ResultsMorphological changes, including decreased presence of lamellipodia and filopodia, were observed in SUSD3 knockdown cells as compared to control at 48 hours. FAK and p-Pax protein levels were increased in SUSD3 knockdown cells as compared to control. Wound healing experiments revealed decreased motility (measured as % wound open) in SUSD3 knockdown cells (95% ± 4%) as compared to control (56% ± 4%). Dispase and aggregation assays revealed decreased cell-to-cell adhesion strength in SUSD3 knockdown cells compared to control.ConclusionIn conclusion, SUSD3 protein appears to play a role in breast cancer cell function as loss leads to decreased motility and adhesion. SUSD3 may be a key functional protein in the metastatic pathway and may prove to be a possible therapeutic target in breast cancer. ObjectiveAromatase inhibitors (AIs) have become the mainstay of the endocrine treatment of postmenopausal breast cancer and we have identified SUSD3 to be down-regulated in AI non-responsive patients. We previously demonstrated a direct regulatory role of ERα in SUSD3 expression with localization of SUSD3 to the outer cellular membrane. We hypothesized a possible role of SUSD3 in breast cancer cell-to-cell adhesion and/or migration. Aromatase inhibitors (AIs) have become the mainstay of the endocrine treatment of postmenopausal breast cancer and we have identified SUSD3 to be down-regulated in AI non-responsive patients. We previously demonstrated a direct regulatory role of ERα in SUSD3 expression with localization of SUSD3 to the outer cellular membrane. We hypothesized a possible role of SUSD3 in breast cancer cell-to-cell adhesion and/or migration. DesignBasic science research. Basic science research. Materials and MethodsMCF7 breast cancer cells were transfected with siRNA targeting SUSD3 or a control siRNA. Morphological changes were documented by phase contrast microscopy 48 and 72 hours post-transfection. Western blot analyses for focal adhesion kinase (FAK), Src, and phosphorylated paxillin (p-Pax) were performed after 72 hr of siRNA transfection. Wound healing, dispase, and aggregation assays were performed after 72hr siRNA transfections and results were documented by phase contrast microscopy. MCF7 breast cancer cells were transfected with siRNA targeting SUSD3 or a control siRNA. Morphological changes were documented by phase contrast microscopy 48 and 72 hours post-transfection. Western blot analyses for focal adhesion kinase (FAK), Src, and phosphorylated paxillin (p-Pax) were performed after 72 hr of siRNA transfection. Wound healing, dispase, and aggregation assays were performed after 72hr siRNA transfections and results were documented by phase contrast microscopy. ResultsMorphological changes, including decreased presence of lamellipodia and filopodia, were observed in SUSD3 knockdown cells as compared to control at 48 hours. FAK and p-Pax protein levels were increased in SUSD3 knockdown cells as compared to control. Wound healing experiments revealed decreased motility (measured as % wound open) in SUSD3 knockdown cells (95% ± 4%) as compared to control (56% ± 4%). Dispase and aggregation assays revealed decreased cell-to-cell adhesion strength in SUSD3 knockdown cells compared to control. Morphological changes, including decreased presence of lamellipodia and filopodia, were observed in SUSD3 knockdown cells as compared to control at 48 hours. FAK and p-Pax protein levels were increased in SUSD3 knockdown cells as compared to control. Wound healing experiments revealed decreased motility (measured as % wound open) in SUSD3 knockdown cells (95% ± 4%) as compared to control (56% ± 4%). Dispase and aggregation assays revealed decreased cell-to-cell adhesion strength in SUSD3 knockdown cells compared to control. ConclusionIn conclusion, SUSD3 protein appears to play a role in breast cancer cell function as loss leads to decreased motility and adhesion. SUSD3 may be a key functional protein in the metastatic pathway and may prove to be a possible therapeutic target in breast cancer. In conclusion, SUSD3 protein appears to play a role in breast cancer cell function as loss leads to decreased motility and adhesion. SUSD3 may be a key functional protein in the metastatic pathway and may prove to be a possible therapeutic target in breast cancer.

An alternative cyclodextrin based formulation for oral anticancer drug exemestane: In vitro and cell culture studies

summary Exemestane (EXE) is an irreversible aromatase inactivator used for the treatment of postmenopausal breast cancer. EXE is orally active but its bioavailability is about 5% due to its low solubility in water. It is known that cyclodextrin (CD) complexation enhances oral bioavailability of poorly soluble drugs. Thus, it was aimed to design and develop cyclodextrin complexes containing EXE and prepare a novel tablet formulation to improve aqueous solubility, dissolution and in vitro permeability. Introduction Estrogen suppression is an important approach to the management of hormone-responsive cancer. Therefore, aromatase inhibition is a well-established therapeutic option in postmenopausal, hormone dependent breast cancer [1]. EXE is an orally active aromatase inactivator, which is absorbed 42% from the gastrointestinal tract and preclinical data indicated that the absolute bioavailability was about 5% due to its low solubility in water and the first pass effect through liver [2,3]. Cyclodextrins (CD) are enzymatic degradation products of starch with a hydrophilic outer surface and an apolar cavity. CDs have the ability to interact with poorly water-soluble drugs and drug candidates resulting in an increase in their apparent water solubility and dissolution rates. It is also reported that CDs show permeability enhancer effects and that they can be considered practically nontoxic upon oral administration [4]. In this study, EXE's inclusion complexes were prepared and characterized using different CD derivatives (methyl-β-cyclodextrin (M-β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CD)) and different preparation techniques and consequently a new tablet formulation was developed using the inclusion complex with optimal dissolution and permeation properties. Experimental methods Phase solubility studies: 0, 5,10,15, 20, 25, 30%w/v solutions ofM-β-CD,HP-β-CD andHP-γCD, all in distilled water, were added to 25 mg EXE and magnetically stirred. 7 days after which 1 mL CD drug suspensions from each vials were filtered through 0.45 μm polycarbonate membrane filter fitted in a stainless still filter holder. The experiments were performed with three replications. The filtrates were quantitatively analysed by an HPLCmethod for EXEwhichwas validated previously [5]. The apparent stability constants (K1:1) of the complexes were calculated. Preparation of inclusion complexes: The inclusion complexes of EXE with either methyl-β-cyclodextrin (M-β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CD) were prepared by both kneading and coprecipitation methods [6] and the molar ratio of EXE:CDs were 1:1. Physical mixtures were also prepared. Characterization of inclusion complexes: Differential scanning calorimetry (DSC), Fourier transformationinfrared spectroscopy (FTIR), Proton NMR spectrometry (H NMR), Scanning electron microscopy (SEM), and X-Ray diffractometry were used to characterize both the complexes and the physical mixtures. Preparation of tablet formulation: Since phase solubility studies, solid state characterization techniques and dissolution studies indicate that M-β-CD and kneading method show the optimumresults, a tablet formulationwas developed using EXE:M-β-CD kneaded (MBK) inclusion complex. Avicel pH 102, Sodium Starch Glycolate and Magnesium Stearate were used as tablet excipients. No solubility enhancer was added to the formulation. The tablets were prepared by direct compression method. Dissolution study of inclusion complexes and tablets: Dissolution studies for EXE, EXE complexes, EXE: M-β-CD tablets and Aromasin® tablets were carried out with six replications. The dissolution medium was 900 mL of 0.5% sodium lauryl sulphate solution (SLS) and 900 mL of distilled water at 37 °C. The difference factors (f1) and the similarity factors (f2) were calculated for tablet formulations to compare dissolution profiles. Transport/permeability studies with Caco-2 cells: Caco-2 cell culture studies were performed on EXE, EXE:CD inclusion complexes which were prepared by kneading method with both M-β-CD, HP-β-CD and HP-γ-CD. Apparent permeability coefficient (Papp:cm/s) was calculated. Statistical analysis of data was performed by Kruskal Wallis One Way Variance Analysis. Result and discussion Phase solubility studies showed that the solubility of EXE increased linearly as a function of the CD concentration, a feature of AL-type complexes. K1:1 was found to be 3722.25M-1 forM-β-CD, 3728.16M-1 for HP-β-CD and 3729.22 M-1 for HP-γ-CD. EXE's solubility with M-βCDwas found tobe 513 times better than EXE. Corresponding solubility diagrams of EXE with M-β-CD, HP-β-CD and HP-γ-CD are presented respectively in Fig. 1. Abstracts / Journal of Controlled Release 148 (2010) e74–e84 e83

Aromatase inhibitors in adjuvant endocrine treatment of breast cancer: ending the debate of sequence or upfront?——interpretation of BIG 1-98 clinical trial

The third generation of aromatase inhibitors (AI) play an important role in the adjuvant treatment of hormonal positive postmenopausal breast cancer. Compared with tamoxifen, either upfront or sequential using of Al can both significantly improve the outcome of breast cancer patients. However, there is a continuous debate of sequence or upfront usage of Al in clinical applications. With the publication result of BIG 1-98 clinical trial and interpretation of the data, we can further recognize and optimize the usage of Al in breast cancer treatment. Key words: Breast neoplasms; Aromatase inhibitors; Neoadjuvant therapy

Abstract A59: A randomized, 3-arm placebo-controlled phase II presurgical trial of celecoxib or exemestane in postmenopausal breast cancer patients: preliminary results

Abstract A59 The presurgical model is a useful tool to screen and evaluate drug activity and select new chemopreventive agents. Cancer cell proliferation measured by ki-67 is considered to be a reliable surrogate biomarker in assessing the efficacy of chemopreventive agents. Exemestane (Exe), a highly specific steroidal aromatase inactivator, has shown clinical efficacy in the treatment of postmenopausal breast cancer (BC) patients. Epidemiologic evidence suggests that anti-inflammatory drugs reduce the risk of BC. Celecoxib (Cel) is a selective inhibitor of the enzyme COX-2 (Cyclooxygenase-2), which is overexpressed in human breast tumors, BC cell lines, and rodent mammary tumors, and it has shown significant antiproliferative and proapoptotic properties. No clinical data are known so far on the antiproliferative activity of Cel in breast cancer cells. The primary endpoint of the present study is to assess the antiproliferative activity (as measured by ki-67 percentage change) of Exe 25mg/d or Cel 800 mg/d relative to placebo in postmenopausal ER positive BC patients treated for 6 weeks before surgery. Estimating a 20% increase in the placebo arm and a 25 % decrease in the treatment arms with 80% power and two-tailed significance at 5 %, a total of 90 subjects (18 in the placebo arm and 36 in each treatment arm) was required. Secondary endpoints were changes in ER and PgR expression, apoptosis, gene expression profile focusing on nuclear receptor coregulators (AIB1, SRC1, TIF-2/GRIP1, N-CoR and SMRT) on frozen tissue, circulating biomarkers (sex hormones, markers of inflammation and hemostasis, insulin-like growth factors, bone markers) and genomic DNA analyses of genetic polymorphisms related to BC, hormone metabolism, response to DNA damage, and cardiovascular events. One hundred and one patients were randomized to either Exe 25 mg/d (n=41), or Cel 800 mg/d (n=40) or placebo (n=20). Baseline median age and BMI were 62, 65, 61 years, 26, 25, 27 in the Exe, Cel and placebo group, respectively. At baseline median ki67% was 21, 18, 18 in the Exe, Cel and placebo arm, respectively. After adjustment for baseline values, Ls means of changes of ki67 were -11.5 (-14.1, -8.9), 1.3 (-1.4, 3.9), 3.2 (-0.5, 6.8) (P among arms <.001; P among active treatments <.001). After adjustment for baseline values, ls means of changes of PgR were -26.2 (-34.1, -18.4), -6.3 (-14.3, 1.7), 2.1 (-8.8, 13.1) (P among arms <.001; P among active treatments <.001). After adjustment for baseline values, ls means of changes of ER were -2.6 (-7.8, 2.7), 0.8 (-4.5, 6.1), -0.7 (-8.0, 6.7) (P among arms 0.671; P among active treatments 0.374). Compliance was higher than 75% and no severe AEs were observed. In this postmenopausal population, Exe has shown a significant reduction of cell proliferation and PgR expression. Bone biomarkers are currently being measured as long as the other secondary endpoints and final results will be helpful to plan further prevention studies with Exe in high-risk subjects. Conversely, only a modest non significant modulation of PgR expression was observed in the Cel arm despite the relatively high dose of the drug. Evaluation of secondary endpoints, including expression of Cox-2 activity, will help to better elucidate the activity of both agents. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A59.

Abstract B19: Aromatase inhibitor therapy, musculoskeletal symptoms and associations with vitamin D and C-reactive protein concentrations

Abstract B19 Background Aromatase inhibitors are widely used for the treatment of post-menopausal breast cancer. Arthralgias and myalgias are major side effects. A case-control study was conducted to determine the prevalence and severity of musculoskeletal symptoms among women treated with aromatase inhibitors compared to women without a history of cancer and to examine the associations between symptoms and concentrations of C-reactive protein (CRP), a marker of systemic inflammation, and serum vitamin D for clues to their underlying etiology. Methods Cases were women undergoing adjuvant treatment for breast cancer with aromatase inhibitors (n = 102). Controls were women without a history of cancer (n = 146). Questionnaires assessed the presence, severity, and location of joint, muscle and bone pain. Participants with pain were asked to rate their pain on average, as well as the degree of pain at its worst, by marking a visual analogue scale. A blood sample was collected and processed within 4 hours of collection with serum stored at -70 degrees centigrade until assayed for vitamin D and CRP concentrations. Analyses were conducted using chi-square tests and unconditional logistic regression adjusting for age and season of blood draw. Results The mean ages of cases and controls were 61.2 and 60.8 years, respectively. After adjustment for age and season of blood draw, cases were more likely than controls to complain of muscle pain (OR 1.75 95% CI 1.00-3.05) and bone pain (OR 1.77 95% CI 0.98-3.20) but not joint pain (OR 0.86; 95% CI 0.46, 1.61). Average pain scores for joint and muscle symptoms were similar between cases and controls but cases rated their average bone pain higher than controls (5.1 versus 3.4; p=0.009). Serum vitamin D and CRP concentrations were not statistically significantly different between cases and controls and were not associated with location or severity of pain. Conclusions Arthralgias and myalgias are common complaints among women, regardless of aromatase inhibitor therapy. Compared to controls, cases described their pain as muscle or bone pain rather than joint pain. These symptoms were not associated with serum vitamin D or CRP concentrations. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B19.

Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial

When the mechanism of action behind treatment toxicity reflects the intended effect on the treatment target, the toxicity might be a useful marker for efficacy. During endocrine treatment of breast cancer, the occurrence of symptoms related to oestrogen depletion or oestrogen blockade might thus be a predictor of treatment effectiveness. In this retrospective analysis, the relation between the reported incidence of vasomotor or joint symptoms and breast cancer recurrence in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial is assessed. Women with hormone-receptor-positive tumours who reported vasomotor or joint symptoms at the first follow-up visit (3 months) in the ATAC trial, (which assessed tamoxifen or anastrozole for adjuvant treatment of postmenopausal breast cancer), were compared with women without these symptoms to see if there was a relation between these symptoms and subsequent recurrence. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. 1486 of 3964 (37.5%) eligible women reported newly emergent vasomotor symptoms at the 3-month follow-up visit and had lower subsequent recurrence than those who did not report these symptoms (223 during 10 752 women-years of follow-up vs 366 during 11 573 woman-years of follow-up, respectively; hazard ratio [HR] 0.84 [95% CI 0.71-1.00], p=0.04; adjusted for age, body-mass index, previous hormone-replacement therapy, nodal status, tumour size, and tumour grade). A greater decrease in breast-cancer recurrence was seen for the 1245 of 3964 (31.4%) eligible women who reported new joint symptoms at the 3-month follow-up visit compared with those not reporting these symptoms (158 during 9242 women-years of follow-up vs 366 during 11 573 women-years of follow-up; adjusted HR 0.60 [0.50-0.72], p<0.0001). The appearance of new vasomotor symptoms or joint symptoms within the first 3 months of treatment is a useful biomarker, suggesting a greater response to endocrine treatment compared with women without these symptoms. Awareness of the relation between early treatment-emergent symptoms and beneficial response to therapy might be useful when reassuring patients who present with them, and might help to improve long-term treatment adherence when symptoms cannot be alleviated effectively.

O-283: Comparative potency of anastrozole to suppress estradiol levels in breast cancer patients undergoing controlled ovarian stimulation prior to IVF: A pilot dose-finding study

Aromatase inhibitors (AI) have been utilized for the treatment of postmenopausal breast cancer with anastrozole being 2.5 times more potent than letrozole on mg basis. Recently letrozole has been used for ovulation induction and controlled ovarian hyperstimulation (COH) prior to in vitro fertilization (IVF) in patients with breast cancer to reduce the estrogen exposure. The aim of this study was to investigate the efficacy of anastrozole for suppressing estradiol (E2) levels in patients during COH compared to those who underwent ovarian stimulation with letrozole.

Towards optimal endocrine therapy for hormone-sensitive breast cancer: Initial versus sequential adjuvant aromatase inhibition

Patients with hormone-receptor-positive early breast cancer have a significant risk of recurrence despite the use of adjuvant tamoxifen. The third-generation aromatase inhibitors letrozole, anastrozole, and exemestane offer promise as alternative or additional therapy to tamoxifen. As extended adjuvant therapy following completion of 5 years of tamoxifen, letrozole further decreased the risk of recurrence compared with placebo. Compared with tamoxifen, both letrozole and anastrozole significantly reduced the risk of recurrence when used as initial adjuvant therapy, and in the short term both were better tolerated than tamoxifen. Anastrozole and exemestane both reduced the risk of relapse when started after 2–3 years of tamoxifen compared with continued tamoxifen treatment; the results of letrozole in this setting are expected in 2008. These data establish adjuvant aromatase inhibitors as effective alternatives to tamoxifen. Only limited data are currently available to inform the choice between an aromatase inhibitor as either initial adjuvant therapy or sequentially after tamoxifen. Future results from the Breast International Group (BIG) 1–98 trial will further clarify strategies for the adjuvant use of aromatase inhibitors. Here, we critically review the evidence for adjuvant use of aromatase inhibitors. Comparison is made between initial aromatase inhibition, switching, and extended adjuvant strategies. Practical recommendations are given for the endocrine treatment of post-menopausal breast cancer.

Treatment of Postmenopausal Breast Cancer with Selective Estrogen Receptor Modulators (SERMs)

Endocrine therapy that targets the estrogen receptor (ER) is a standard of care for the treatment of postmenopausal women with ER-positive breast cancer. The selective ER modulator (SERM) tamoxifen has been in use for the treatment of advanced breast cancer for more than 30 years and is currently a treatment option for all stages of ER-positive disease. Tamoxifen blocks the action of estrogen by binding to the ER, and possesses both ER-agonist and antagonist properties. Unfortunately, long-term use of tamoxifen is associated with several important concerns including an increased risk of endometrial cancer and thromboembolic complications. In addition, many patients who initially respond to tamoxifen eventually relapse with resistant disease. New treatment approaches are therefore required. A number of alternative SERMs have been tested as substitutes for tamoxifen. These include; toremifene, droloxifene, idoxifene, and keoxifene. Unfortunately, the SERMs have not proved to be more effective than tamoxifen for the treatment of advanced breast cancer and have shown a high level of cross-resistance with tamoxifen. The subsequent development of the aromatase inhibitors (AIs) is an important therapeutic advance by creating a "no estrogen" environment. Another approach is the development of pure antiestrogens. Fulvestrant is a novel ER antagonist that destroys the ER and its signaling pathway and is not associated with tamoxifen-like agonist effects. It produces high response rates compared with other SERMs and is not cross-resistant to tamoxifen or aromatase inhibitors and is equally as effective as the AI anastrozole in the treatment of postmenopausal women with advanced breast cancer who have progressed on prior adjuvant tamoxifen therapy. This review article discusses the significant and continuing value of SERMs for the treatment of postmenopausal ER-positive breast cancer.

Genistein alone and in combination with the mammalian lignans enterolactone and enterodiol induce estrogenic effects on bone and uterus in a postmenopausal breast cancer mouse model

The use of phytoestrogens, such as isoflavones and lignans, for treatment of postmenopausal breast cancer is increasing, but their effects on bone and other major organs are not clear. While the isoflavone genistein (GEN) has been shown to prevent or slow the loss of bone mineral density (BMD), the effect of lignans enterodiol (END) and enterolactone (ENL) are unknown. In this study, we determined in ovariectomized mice with human MCF-7 breast tumor xenografts the effects of the lignans, and GEN, alone and in combination, on bone and uterus. Mice with established MCF-7 tumors were fed a basal diet (AIN-93G), divided into 5 groups, and given daily subcutaneous injections (10 mg/kg body weight) of either ENL, END, GEN, a mixture of these compounds (MIX), or vehicle as a negative control for 22 weeks. Results showed that GEN acts estrogenically in both the uterus and bone by increasing the uterus weight, femur BMD, and femur biomechanical strength (yield load), while the lignans do not. However, treatment with MIX induced minimal effects on femur biomechanical strength parameters but significantly increased uterus weight. A significant positive correlation was observed between MCF-7 tumor volume and femur BMD and biomechanical strength parameters (femur peak load and yield load) but not with uterus weight, suggesting that the uterus may respond differently to phytoestrogens compared to MCF-7 tumors and bone. It is concluded that GEN induces beneficial effects on bone but has adverse effects on tumors and uterus in this model of postmenopausal breast cancer. The lignans do not exert adverse effects on any tissue, however, when combined with GEN, they exert an adverse effect on the uterus.

Comparing cost/utility of giving an aromatase inhibitor as monotherapy for 5 years versus sequential administration following 2–3 or 5 years of tamoxifen as adjuvant treatment for postmenopausal breast cancer

Background: Several studies have shown aromatase inhibitors administered as monotherapy or sequentially to tamoxifen to improve relapse-free survival in postmenopausal women with early breast cancer. Any difference in cost/utility between the strategies may be of importance to therapy selection.Methods: Cost/utility was compared between the different regimens based on the theoretical assumption that costs, benefits and side-effects were similar for each drug and independent of whether it was administered as monotherapy or sequentially.Results: Tamoxifen for 2–3 years followed by an aromatase inhibitor for 3 or 2 years provided the lowest cost/quality-adjusted life years (QALY) estimates, while administration of an aromatase inhibitor subsequent to 5 years on tamoxifen provided the highest values. The difference between strategies increased with patient age. Cost/QALY estimates were sensitive to an increase in hip fracture risk and to cost reductions due to relapse prevention. Adding oral bisphosphonates increased costs moderately.Conclusions: While tamoxifen for 2–3 years followed by an aromatase inhibitor provided the lowest cost/QALY estimates, a further improvement of relapse-free survival of 1% if the aromatase inhibitor is given upfront provides an acceptable cost/QALY. In contrast, additional benefits achieved by administering an aromatase inhibitor subsequent to 5 years of tamoxifen provided unacceptable costs.

Neoadjuvant Treatment of Postmenopausal Breast Cancer With Anastrozole, Tamoxifen, or Both in Combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) Multicenter Double-Blind Randomized Trial

The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) trial was designed to test the hypothesis that the clinical and/or biologic effects of neoadjuvant tamoxifen compared with anastrozole and with the combination of tamoxifen and anastrozole before surgery in postmenopausal women with estrogen receptor (ER) -positive, invasive, nonmetastatic breast cancer might predict for outcome in the Arimidex, Tamoxifen Alone or in Combination (ATAC) adjuvant therapy trial. Postmenopausal women with ER-positive, invasive, nonmetastatic, and operable or locally advanced potentially operable breast cancer were randomly assigned to neoadjuvant tamoxifen (20 mg daily), anastrozole (1 mg daily), or a combination of tamoxifen and anastrozole for 3 months. The tumor objective response (OR) was assessed by both caliper and ultrasound. Comparisons were also made of clinical response with ultrasound response, actual and feasible surgery with feasible surgery at baseline, OR in human epidermal growth factor receptor 2 (HER2)-positive cancers, and tolerability. There were no significant differences in OR in the intent-to-treat population between patients receiving tamoxifen, anastrozole, or the combination. In patients who were assessed as requiring mastectomy at baseline (n = 124), 44% of patients received breast-conserving surgery (BCS) after anastrozole compared with 31% of patients after tamoxifen (P = .23); this difference became significant for patients who were deemed feasible for BCS by their surgeon (46% v 22%, respectively; P = .03). The OR for patients with HER2-positive cancer (n = 34) was 58% for anastrozole compared with 22% for tamoxifen (P = .18). All treatments were well tolerated. Neoadjuvant anastrozole is as effective and well tolerated as tamoxifen in ER-positive operable breast cancer in postmenopausal women, but the hypothesis that clinical outcome might predict for long-term outcome in adjuvant therapy was not fulfilled.

Aromatase inhibitors—Socio-economical issues

Novel, third-generation aromatase inhibitors are currently implemented for treatment of postmenopausal breast cancer in the metastatic and adjuvant setting and, potentially, for breast cancer prevention. Introduction of novel therapeutic strategies to large patient groups may add significant costs to health care budgets, forcing institutions to focus entirely on costs or the cost-utility of implementing such novel strategies. Breast cancer is the most frequent cancer in the female population in western societies, and its incidence is currently increasing in other parts of the world as well. Due to the proven efficacy and limited side effects of endocrine therapy in the adjuvant setting, the indications for use have been successively broadened. Currently, the majority of postmenopausal women treated for an estrogen-receptor positive breast cancer will be offered adjuvant endocrine therapy; thus, a general change of practice may cause significant implications to healthcare costs. This may relate to direct drug costs as well as indirect costs related to prevention of side effects, like additional use of bisphosphonates to prevent enhanced bone loss. The aim of this paper is to overview these considerations and put them into perspective by simple illustrations taken from current cost estimates.

Molecular effects of anastrozole (A) and tamoxifen (T) alone and combined (C) in the IMPACT trial of neoadjuvant treatment of primary breast cancer

537 Background: Aromatase inhibitors and tamoxifen are key agents for endocrine treatment of postmenopausal breast cancer (BrCa). Understanding of their molecular/biological effects in BrCa is needed for their rational application alone or in combination with novel therapeutics. Methods: 330 postmenopausal patients with invasive BrCa (>/=2cm) were randomised to 12wks neoadjuvant therapy with A, T or C in a placebo-controlled double-blind trial (IMPACT). Biopsies were available from a total of 292 patients pre-treatment and at 2 and 12 wks. Immunohistochemical (IC) studies were performed for Ki67, apoptosis (TUNEL), ER, PgR, EGFR (pre) and HER2 (pre). The growth index (GI: Ki67/apoptosis) was calculated. Plasma estradiol (E2) levels were measured. Results: The %age changes in the biomarkers from baseline are shown in the table. IC results for T and C were similar in all respects. The greater reductions in Ki67 in A vs T have been reported. There were greater reductions in GI for A vs T despite the decreases in apoptosis seen with A and profound differences between the treatments in their effect on PgR. After 2wks the reduction in PgR for A, and the increase in PgR for T were correlated with the fall in Ki67 (p=0.003 and 0.027, respectively). After 12wks there was a significantly lower reduction in Ki67 in HER2+ vs HER2- tumours (geo mean: 73% vs 48%) but no significant difference between the treatment groups. Conclusions: Changes in both Ki67 and GI parallel the greater reduction in relapse rate for A vs T and C in the ATAC adjuvant trial. This suggests short-term biomarker changes may predict for long-term outcome in the adjuvant setting but this needs confirmation. The decrease in apoptosis seen with A suggests that estrogen is not an important survival factor in BrCa cells. Early increases in PgR with T are not associated with a poor antiproliferative effect. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Astrazeneca AstraZeneca

Molecular effects of anastrozole (A) and tamoxifen (T) alone and combined (C) in the IMPACT trial of neoadjuvant treatment of primary breast cancer

537 Background: Aromatase inhibitors and tamoxifen are key agents for endocrine treatment of postmenopausal breast cancer (BrCa). Understanding of their molecular/biological effects in BrCa is needed for their rational application alone or in combination with novel therapeutics. Methods: 330 postmenopausal patients with invasive BrCa (>/=2cm) were randomised to 12wks neoadjuvant therapy with A, T or C in a placebo-controlled double-blind trial (IMPACT). Biopsies were available from a total of 292 patients pre-treatment and at 2 and 12 wks. Immunohistochemical (IC) studies were performed for Ki67, apoptosis (TUNEL), ER, PgR, EGFR (pre) and HER2 (pre). The growth index (GI: Ki67/apoptosis) was calculated. Plasma estradiol (E2) levels were measured. Results: The %age changes in the biomarkers from baseline are shown in the table. IC results for T and C were similar in all respects. The greater reductions in Ki67 in A vs T have been reported. There were greater reductions in GI for A vs T despite the decreases in apoptosis seen with A and profound differences between the treatments in their effect on PgR. After 2wks the reduction in PgR for A, and the increase in PgR for T were correlated with the fall in Ki67 (p=0.003 and 0.027, respectively). After 12wks there was a significantly lower reduction in Ki67 in HER2+ vs HER2- tumours (geo mean: 73% vs 48%) but no significant difference between the treatment groups. Conclusions: Changes in both Ki67 and GI parallel the greater reduction in relapse rate for A vs T and C in the ATAC adjuvant trial. This suggests short-term biomarker changes may predict for long-term outcome in the adjuvant setting but this needs confirmation. The decrease in apoptosis seen with A suggests that estrogen is not an important survival factor in BrCa cells. Early increases in PgR with T are not associated with a poor antiproliferative effect. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Astrazeneca AstraZeneca

Aromatase inhibitors: current indications and future prospects for treatment of postmenopausal breast cancer.

This article provides a comprehensive review of aromatase inhibitors (AIs) for geriatricians, because it appears that more elderly women will be using these drugs in the near future. Computerized literature searches of Medline were conducted through May 2003. Key words/phrases included in the literature searches were aromatase inhibitors, estrogen, and breast cancer. Limits included English language, age 65 and older, and female sex. All relevant articles were selected and reviewed. AIs suppress intratumoral and plasma estrogen levels significantly. Third-generation AIs have excellent pharmacological profiles, with no significant drug interactions and better tolerability. These drugs have shown superiority compared with conventional therapies. The results of anastrozole, tamoxifen, and combination trials favors anastrozole over tamoxifen for adjuvant treatment, but further follow-up is required. AIs are approved for the treatment of advanced metastatic breast cancer (BC) in postmenopausal women whose disease has progressed during tamoxifen therapy. Recent trials have shown that the highly selective third-generation AIs are effective when used as first-line therapy in metastatic BC. Their possible use in preventive, adjuvant, and neoadjuvant settings is also being explored.

Tamoxifen and Megestrol Acetate for Postmenopausal Breast Cancer: Diverging Effects on Liver Proteins, Androgens, and Glucocorticoids

To compare the effects of tamoxifen and megestrol acetate on liver proteins, androgens, and glucocorticoids during adjuvant treatment for postmenopausal breast cancer. A subgroup of women within a large prospective multicenter trial were followed with blood sampling every 3 mo during 2 yr. Women were randomized to receive either continuous tamoxifen 40 mg/d or repeated sequential treatment with tamoxifen and megestrol acetate (MA) 160 mg/d. We found profound and distinct differences between the two regimens. Tamoxifen increased steroid-binding proteins (SHBG and CBG) and suppressed circulating androgens and IGF-I. In contrast, the metabolic effects of tamoxifen were clearly antagonized by MA. There was a rise in IGF-I and marked suppression of steroid-binding proteins. Levels of free testosterone were reduced by 70%. MA also caused apparent adrenal suppression. The different effects on anabolic/catabolic balance and adrenal function may relate to certain clinical effects during treatment.

Aromatase Inhibitors and Inactivators for the Treatment of Postmenopausal Breast Cancer: A Review

Breast cancer is often an estrogen dependent disease and several endocrine treatment options are well established in clinical practice. Although ovarian estrogen synthesis ceases at menopause, estrogens may still be produced by the aromatization of androgens. The “aromatase-pathway” is the major (and probably only) source of estrogens in postmenopausal women. While the antiestrogen tamoxifen has dominated the field of endocrine treatment of breast cancer for decades, novel aromatase inhibitors and inactivators have recently challenged the position of tamoxifen. Non-steroidal aromatase inhibitors like anastrozole and letrozole as well as the aromatase inactivator exemestane have shown to have advantages compared to the traditional drugs like tamoxifen and megestrol acetate. Currently, the aromatase inhibitors and inactivators mentioned above are going to be established as first-line treatment in postmenopausal women with hormonesensitive, metastatic breast cancer. In addition, aromatase inhibitors and inactivators have the potential to be used in the adjuvant setting as well as in breast cancer prevention. This publication gives an overview about the experience made with the most important aromatase inhibitors and inactivators in all stages of hormone-dependent breast cancer focusing on the compounds belonging to the so-called “third generation”: anastrozole, letrozole and exemestane.

Aromatase inhibitor development and hormone therapy: a perspective

The introduction of aromatase inhibitors as a new class of agents represents a further step in improving breast cancer treatment and possibly in preventing this disease. Although these agents are now used in the first- and second-line treatment of postmenopausal breast cancer, the heterogeneity of patients enrolled in clinical trials prevents a thorough assessment of the effectiveness of potential sequential and combination therapies. Such investigations are more easily performed in the laboratory, and to this end, a tumor model in nude mice was established to simulate several aspects of the postmenopausal breast cancer patient. This model showed that aromatase inhibitors are more efficient than tamoxifen at reducing tumor volume. Additionally, the combination of an aromatase inhibitor plus tamoxifen does not improve the antiproliferative results obtained with the aromatase inhibitor alone, a finding corroborated in the Arimidex, Tamoxifen Alone or in Combination adjuvant clinical trial. To investigate the effect that potential sequences of treatment have on tumor growth, letrozole was administered in sequence with tamoxifen to nude mice bearing human xenografts. Tumor growth was significantly reduced with the sequence compared with tamoxifen alone. Additionally, when agents were alternated every 4 weeks, mice started on letrozole fared better than those started on tamoxifen. Finally, letrozole alone provided the best and most sustained reduction in tumor growth. These experiments suggest the means to evaluate therapeutic combinations in the laboratory to guide potential trial designs and provide the best chance of success to the patients who enter these clinical trials.