First-line Treatment Of Postmenopausal Women Research Articles

PHARMACOECONOMIC EVALUATION OF RIBOCICLIB FOR THE FIRST-LINE TREATMENT OF HR-POSITIVE HER2-NEGATIVE ADVANCED BREAST CANCER

Background.Breast cancer is the most common malignant tumor and accounts for the most number of cancer-related deaths among Russian women. Combination of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor ribociclib and aromatase inhibitor is approved for the first-line treatment of postmenopausal women with HR-positive HER2-negative advanced breast cancer.Objective:to conduct pharmacoeconomic evaluation of using ribociclib + aromatase inhibitor for the first-line treatment of HR-positive HER2- negative advanced breast cancer from the Russian healthcare system perspective.Materials and methods.The comparator was palbociclib + aromatase inhibitor, because ribociclib and palbociclib have similar mechanism of action and are the only available CDK4/6 inhibitors that could be used for treatment of HR-positive HER2-negative advanced breast cancer in Russia. Using clinical trials data and published results of matching adjusted indirect comparison (MAIC), we proposed Markov chain model of breast cancer progression and estimated direct medical costs associated with two considered options (first and subsequent lines of drug therapy, adverse events treatment, inpatient and outpatient care). Budget impact and cost-effectiveness analyses were conducted. Mean duration of treatment in the model was 21,9 and 20,2 months on ribociclib and palbociclib for five year time horizon respectively.Results and conclusion.Monthly medication costs of ribociclib (270 814.18 RUB) were 9 % less than for palbociclib (296 517.21 RUB). Driven by less monthly medication costs and potential of cost reduction due to dose reduction, five-year total medical per patient costs for ribociclib were 4 991 168 RUB, which were 1 162 666 RUB or 19 % less than for palbociclib. Ribociclib also had better (lower) cost/effectiveness ratio (1 244 906 vs 1 595 867 RUB per life year). As the result, ribociclib was considered a cost-saving option. If 8 162–8 270 women receive ribociclib, public healthcare expenditures will decrease by 20.1 billion RUB (21 %) within 3 years, compared to palbociclib.

Anti-tumor efficacy of new 7α-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells

The majority of breast cancer cases are estrogen receptor positive (ER+). Although, third-generation aromatase inhibitors (AIs) are used as first-line treatment in post-menopausal women, they cause endocrine resistance and bone loss, which limits their success. Therefore, there is a demand to discover new potent molecules, with less toxicity that can circumvent these drawbacks. Our group has previously demonstrated that new 7α-substituted steroidal molecules, 7α-(2ξ,3ξ-epoxypropyl)androsta-1,4-diene-3,17-dione (3), 7α-allylandrost-4-ene-3,17-dione (6), 7α-allylandrost-4-en-17-one (9), 7α-allyl-3-oxoandrosta-1,4-dien-17β-ol (10) and 7α-allylandrosta-1,4-diene-3,17-dione (12) are potent AIs in placental microsomes. In this work, it was investigated their anti-aromatase activity and in vitro effects in sensitive and resistant breast cancer cells. All the steroids efficiently inhibit aromatase in breast cancer cells, allowing to establish new structure-activity relationships for this class of compounds. Moreover, the new AIs can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of AIs 3 and 12 on sensitive cells were dependent on aromatase inhibition and androgen receptor (AR), while for AI 9 and AI 10 were AR- and ER-dependent, respectively. In addition, it was shown that all the AIs can sensitize resistant cancer cells being their behavior similar to the sensitive cells. In summary, this study contributes to the understanding of the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. In addition, allowed the discovery of new potent 7α-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance.

Use of anastrozole in the chemoprevention and treatment of breast cancer: A literature review.

Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.

Efficacy of Letrozole as First-Line Treatment of Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer in Korea.

PurposeLetrozole showed efficacy and generally favorable toxicities, along with the convenience of oral administration in postmenopausal patients with hormone receptor (HR)–positive metastatic breast cancer (MBC). To the best of our knowledge, there have been no reports of the clinical outcomes in Korean patients, although letrozole is widely used in practice. Therefore, this studywas conducted to affirm the efficacy and toxicities of letrozole in Korean patients.Materials and MethodsThis study retrospectively analyzed 84 HR-positive MBC patients who had been treated with letrozole from January 2001 to December 2012. Clinicopathological characteristics and treatment history were extracted from medicalrecords. All patients received 2.5 mg letrozole once a day until there were disease progressions or unacceptable toxicity. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and toxicity.ResultsThe median age of the subjects was 59.3 years. Letrozole treatment resulted in a median PFS of 16.8 months (95% confidence interval [CI], 9.8 to 23.8) and a median OS of 56.4 months (95% CI, 38.1 to 74.7). The ORR was 36.9% for the 84 patients with measurable lesions. Multivariate analysis revealed symptomatic visceral disease (hazard ratio, 3.437; 95% CI, 1.576 to 7.495; p=0.002) and a disease-free interval ≤ 2 years (hazard ratio, 2.697; 95% CI, 1.262 to 5.762; p=0.010) were independently associated with shorter PFS. However, sensitivity to adjuvant hormone treatment was not related to PFS. Letrozole was generally well tolerated.ConclusionLetrozole showed considerable efficacy and tolerability as a first-line treatment in postmenopausal patients with HR-positive MBC.

442O - Cell Cycle Biomarker Analysis from the Paloma-1/ Trio 18 Palbociclib Plus Letrozole Phase Ii Study in Er-Positive/Her2-Negative Advanced Breast Cancer (Abc)

ABSTRACT Aim: Palbociclib (P) is a highly selective, reversible inhibitor of CDK 4/6. Preclinical data identified breast cancer cell lines representing ER+ luminal breast cancer as more sensitive to the anti-proliferative effects of P and with lower levels of CDKN2A and higher levels of Rb and CCND1 by RNA expression. Based on these data, a phase 2 randomized study of P plus letrozole (P + L) vs. L alone in the first-line treatment of postmenopausal women with ER + /HER2- ABC was conducted. Final results demonstrated a significant improvement in progression-free survival (PFS) with P + L (HR = 0.488; 95% CI 0.319-0.748, p = 0.0004) (Finn et al AACR 2014). We assessed potential biomarkers both retrospectively and prospectively, and their relationship with PFS. Methods: 165 patients were randomized. CCND1 and CDKN2A copy numbers were determined by four-color FISH assay. The expressions of pRb, CCND1, and Ki67 were measured by validated IHC assays at central laboratories. Results: The study consisted 2 parts. Part 1 (N = 66) enrolled patients (pts) with ER + /HER2- ABC. 46 of 66 pts had tissue available for retrospective CCND1 and CDKN2A FISH analysis. 21 pts were biomarker positive (BM+) (CCND1/CEP11 ratio ≥ 1.5 and/or CDKN2A/CEP9 ratio 20% vs. ≤20% were observed. 80 /165 pts had tissue for cyclin D1 and pRb protein IHC. 73/79 (92.4%) and 73/77 (94.8%) were positive for cyclin D1 and pRb, respectively. Conclusions: P + L provides a consistent benefit in ER + /HER2- ABC compared to L alone. Both BM+ and BM- pts benefited from P + L. Ki67 staining did not identify a subgroup that benefited more from P + L. As expected, over 90% of the pts analyzed stained positive for pRb and cyclin D1. Disclosure: Y. Jiang, S. Randolph, P. English, S. Kim and X. Huang: Employment: Pfizer; D. Slamon and R.S. Finn:: Research Support: Pfizer. All other authors have declared no conflicts of interest.

Prevalence of renal impairment among osteoporotic women in the USA, NHANES 2005–2008: Is treatment with bisphosphonates an option?

Bisphosphonates are the first-line treatment for osteoporotic (OP) women; however, therapy is not recommended in severe renal impairment (RI). This study examined RI prevalence among OP women. Nearly a quarter of women had moderate RI, and 3.59% would not be recommended for bisphosphonates, demonstrating a need for better therapeutic alternatives. Bisphosphonates are the recommended first-line treatment for postmenopausal women with OP. However, bisphosphonates are cleared through the kidney, and therapy is not recommended in severe RI due to adverse treatment effects observed with intravenous formulations. The objective of this study was to examine the prevalence of RI among women with OP aged ≥50 years in the USA. Women with OP aged ≥50 years were identified using the 2005-2008 National Health and Nutrition Examination Survey (NHANES) data. OP was defined as prior OP diagnosis, previous hip or spine fracture, or measured lumbar spine/femoral neck bone mineral density (BMD) T-score <-2.5. The 2005 Modification of Diet in Renal Disease (MDRD) formula was used to calculate the glomerular filtration rate (GFR). Moderate and severe RI was defined as GFR 30-59 and 15-29 mL/min, respectively. Bisphosphonate therapy was considered not recommended among women with OP if GFR was <35 mL/min. The prevalence of OP among women in USA aged ≥50 years was 27% (12.7 million). Nearly a quarter of women with OP (23.54 ± 2.02%; 2.9 million) had moderate RI and 1.88 ± 0.28% (230,000) had severe RI. Correspondingly, bisphosphonate therapy would not be recommended for an estimated 439,000 women with OP (3.59 ± 0.73%). Nearly a quarter of postmenopausal women with OP have moderate RI, and over 3% would not be recommended for bisphosphonate treatment. These data reveal a need for better therapeutic alternatives that can be used in this patient population.

Proteomic Signatures of Acquired Letrozole Resistance in Breast Cancer: Suppressed Estrogen Signaling and Increased Cell Motility and Invasiveness

Aromatase inhibitors, such as letrozole, have become the first-line treatment for postmenopausal women with estrogen-dependent breast cancer. However, acquired resistance remains a major clinical obstacle. Previous studies demonstrated constitutive activation of the MAPK signaling, overexpression of HER2, and down-regulation of aromatase and ERα in letrozole-resistant breast cancer cells. Given the complex signaling network involved in letrozole-refractory breast cancer and the lack of effective treatment for hormone resistance, further investigation of aromatase inhibitor resistance by a novel systems biology approach may reveal previously unconsidered molecular changes that could be utilized as therapeutic targets. This study was undertaken to characterize for the first time global proteomic alterations occurring in a letrozole-resistant cell line. A quantitative proteomic analysis of the whole cell lysates of LTLT-Ca (resistant) versus AC-1 cells (sensitive) was performed to identify significant protein expression changes. A total of 1743 proteins were identified and quantified, of which 411 were significantly up-regulated and 452 significantly down-regulated (p < 0.05, fold change > 1.20). Bioinformatics analysis revealed that acquired letrozole resistance is associated with a hormone-independent, more aggressive phenotype. LTLT-Ca cells exhibited 84% and 138% increase in migration and invasion compared with the control cells. The ROCK inhibitor partially abrogated the enhanced migration and invasion of the letrozole-resistant cells. Flow cytometric analyses also demonstrated an increase in vimentin and twist expression in letrozole-resistance cells, suggesting an onset of epithelial to mesenchymal transition (EMT). Moreover, targeted gene expression arrays confirmed a 28-fold and sixfold up-regulation of EGFR and HER2, respectively, whereas ERα and pS2 were dramatically reduced by 28-fold and 1100-fold, respectively. Taken together, our study revealed global proteomic signatures of a letrozole-resistant cell line associated with hormone independence, enhanced cell motility, EMT and the potential values of several altered proteins as novel prognostic markers or therapeutic targets for letrozole resistant breast cancer.

342P - Fulvestrant (FUL) Plus Enzastaurin (ENZA) vs FUL Plus Placebo (PBO) in Aromatase Inhibitor (AI)-Resistant Metastatic Breast Cancer (MBC): A Randomized, Double-Blind, Phase 2 Trial

ABSTRACT Disclosure K. Mansouri: K. Mansouri is an employees of Eli Lilly and Co. L. Cirri: L. Cirri is an employees of Eli Lilly and Co. P. Shi: P. Shi is an employees of Eli Lilly and Co. O. Hamid: O. Hamid is an mployees of Eli Lilly and Co. All other authors have declared no conflicts of interest. AIs are used as first-line treatment for postmenopausal women with hormone-receptor-positive MBC. Overexpression of PKC α has been linked to AI resistance in several studies. We examined whether Enza, a serine/threonine kinase inhibitor that targets PKC, could improve the effect of Ful in pts who progressed following first-line AI treatment for MBC. Postmenopausal pts with hormone-receptor-positive, HER2-negative, locally advanced or MBC who progressed on prior AI received a loading dose of Ful 500 mg IM on Day (D) 1 and 250 mg on D 15 of Cycle (C) 1 and D 1 of each cycle thereafter. Enza 500 mg or PBO was administered orally once daily (QD) or 250 mg twice daily (BID). Primary endpoint was the clinical benefit rate (CBR). Secondary endpoints were response rate (RR), duration of CB, progression-free survival (PFS) and safety. A total of 156 pts was randomly assigned to therapy; 152 received at least 1 dose of study drug (39 BID; 55 QD; 58 PBO). Baseline disease characteristics were balanced across arms. There was no statistically significant difference in CBR between pts in Ful + Enza vs Ful + PBO. There was no statistically significant difference in CBRs, RRs and PFS between pts on QD and BID dosing schedules. Pts on BID dosing had numerically more TEAEs vs those on QD and PBO (61.5%, 43.6%, and 46.6%, respectively) and numerically more Grade 3/4 TEAEs vs QD and PBO (17.9%, 9.1%, and 5.2%, respectively). Most frequent Grade 3/4 TEAEs in the BID arm were fatigue (n [%]) (4 [10.3%]), dyspnea (2 [5.1%]) and nausea (2 [5.1%]). 8 pts died; 5 due to disease, 3 due to AEs: 1 drug-related hepatic dysfunction (Enza QD arm), 1 non-drug-related myocardial infarction and 1 non-drug-related respiratory failure (both in the Enza BID arm). Ful + Enza [QD + BID] N = 94 Ful + PBO N = 58 P-value vs PBO CBR Number of responders, n (%), (95% CI) 41 (43.6) (33.4, 54.2) 24 (44.8) (31.7, 58.5) 0.62 RR, % (95% CI) 5.3 (1.7, 12.0) 5.2 (1.1, 14.4) 0.64 PFS, months (95% CI) 5.2 (3.5, 7.4) 5.5 (3.8, 7.4) 0.59 Median duration of CB, months 9.6 9.7 0.86 CBR = complete response + partial response + stable disease Addition of Enza to Ful does not improve disease outcome in pts with locally advanced or MBC after progression on AI.

Cost Effectiveness of Denosumab Compared with Oral Bisphosphonates in the Treatment of Post-Menopausal Osteoporotic Women in Belgium

Denosumab has recently been shown to be well tolerated, to increase bone mineral density (BMD) and to significantly reduce the risk of hip, vertebral and non-vertebral fractures in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial. It is becoming increasingly important to evaluate not only the therapeutic value of a new drug but also the cost effectiveness compared with the most relevant treatment alternatives. The objective of this study was to estimate the cost effectiveness of denosumab compared with oral bisphosphonates (branded and generic drugs) in the treatment of post-menopausal osteoporotic women in Belgium. Cost effectiveness of 3 years of treatment with denosumab was compared with branded risedronate and branded and generic alendronate using an updated version of a previously validated Markov microsimulation model. The model was populated with relevant cost, adherence and epidemiological data for Belgium from a payer perspective and the results were presented as costs per QALY gained (&U20AC;, year 2009 values). Analyses were performed in populations (aged ≥60 years) in which osteoporosis medications are currently reimbursed in many European countries, i.e. those with BMD T-score of -2.5 or less or prevalent vertebral fracture. Patients receiving denosumab were assumed to have a 46% lower risk of discontinuation than those receiving oral bisphosphonates, and the effect of denosumab after treatment cessation was assumed to decline linearly to zero over a maximum of 1 year. Denosumab was cost effective compared with all other therapies, assuming a willingness to pay of &U20AC;40 000 per QALY gained. In particular, denosumab was found to be cost effective compared with branded alendronate and risedronate at a threshold value of &U20AC;30 000 per QALY and denosumab was dominant (i.e. lower cost and greater effectiveness) compared with risedronate from the age of 70 years in women with a T-score of -2.5 or less and no prior fractures. The cost effectiveness of denosumab compared with generic alendronate was estimated at &U20AC;38 514, &U20AC;22 220 and &U20AC;27 862 per QALY for women aged 60, 70 and 80 years, respectively, with T-scores of -2.5 or less. The equivalent values were &U20AC;37 167, &U20AC;19 718 and &U20AC;19 638 per QALY for women with prevalent vertebral fractures. This study suggests, on the basis of currently available data, that denosumab is a cost-effective strategy compared with oral bisphosphonates (including generic alendronate) for the treatment of post-menopausal osteoporotic women, aged ≥60 years in Belgium. Denosumab therefore appears to have the potential to become a first-line treatment for post-menopausal women with osteoporosis. However, further studies would be required to evaluate the long-term safety and adherence of denosumab in real-world clinical practice as well as head-to-head effectiveness compared with oral bisphosphonates.

Bosutinib (BOS) and letrozole (LET) versus LET alone as first-line treatment in postmenopausal women with advanced breast cancer (ABC).

614 Background: BOS (SKI-606) is an orally active, dual Src/Abl tyrosine kinase inhibitor. Elevations of Src activity occur in ~60% of breast tumors and correlate with tumor aggressiveness. A prior...

Abstract S1-3: A Comparison of Fulvestrant 500 mg with Anastrozole as First-Line Treatment for Advanced Breast Cancer: Follow-Up Analysis from the ‘FIRST’ Study

Abstract Background: Fulvestrant 250 mg has been shown to be at least as effective as anastrozole as second-line endocrine therapy for advanced hormone receptor-positive (HR+) breast cancer. However, there are biological and clinical data suggesting that fulvestrant 500 mg is more effective than 250 mg. The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was designed to compare fulvestrant 500 mg with anastrozole in the first-line setting. The primary analysis reported that fulvestrant 500 mg was at least as effective as anastrozole in terms of clinical benefit rate and objective response rate. At data cut-off for the primary analysis, performed 6 months after the last patient (pt) was randomized, 117 (57.1%) pts were receiving study treatment, and median time to progression (TTP) was not reached for fulvestrant 500 mg vs 12.5 months for anastrozole (HR 0.63; 95% CI 0.39, 1.00; p=0.0496). Here, we report a follow-up data analysis of TTP and time to treatment failure (TTF). Methods: This was a Phase II, randomized, open-label, multicenter study comparing fulvestrant 500 mg (500 mg i.m. on Day 0, then 500 mg i.m. on Days 14 and 28 and every 28 days thereafter) with anastrozole (1 mg/day p.o.) as first-line treatment for postmenopausal women with advanced breast cancer. Follow-up analysis was performed when 79.5% of pts had discontinued study treatment. TTP was defined by RECIST before data cut-off for the primary analysis, and investigator opinion after data cut-off. TTF was defined as time from randomization to cessation of trial therapy. In the fulvestrant 500 mg group, TTF was derived as last injection plus 14 days, representing the midpoint in the window where treatment was withdrawn. Best overall response to first subsequent breast cancer therapy, WHO-PS, and serious AEs are also reported. Results: A total of 205 pts received fulvestrant 500 mg (n=102) or anastrozole (n=103). At this follow-up analysis with data cut-off March 26 2010, median follow-up for TTP across both treatment groups was 16.5 months. Median TTP was 23.4 months for the fulvestrant 500 mg group vs 13.1 months for the anastrozole group, corresponding to a 35% reduction in risk of progression (HR 0.66; 95% CI 0.47, 0.92; p=0.01). Median TTF was 17.6 months vs 12.7 months for the fulvestrant 500 mg and anastrozole groups, respectively (HR 0.73; 95% CI 0.54, 1.00; p=0.05). The best overall response to subsequent therapy was similar between the treatment groups (including 15 pts [23.8%] in the fulvestrant 500 mg group and 15 pts [21.1%] in the anastrozole group with either a complete or partial response) and there were no clinically important differences in terms of WHO-PS. Fulvestrant 500 mg was well tolerated and no new safety concerns were documented. Conclusion: With significantly longer follow-up, the TTP and TTF results from this analysis are consistent with the analysis of TTP at the primary data cut-off. Taken together, these results suggest an efficacy benefit for fulvestrant 500 mg compared with anastrozole as first line endocrine therapy for pts with HR+ advanced breast cancer. These data provide further support that if fulvestrant is used in advanced breast cancer then the preferred dose should be 500 mg. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-3.

Indirect comparison of the cost-effectiveness of letrozole plus lapatinib (LET+LAP) versus anastrozole plus trastuzumab (ANA+TZ) as first-line treatment for postmenopausal women with HER2+ and HR+ metastatic breast cancer (MBC) from the U.K. National Health Service (NHS) perspective.

1035 Background: The EGF30008 trial assessed the efficacy of the combination of the anti-HER2 tyrosine kinase inhibitor LAP and the aromatase inhibitor (LET) compared with LET plus placebo in postmenopausal women with HER2+ and HR+ MBC. The TAnDEM study evaluated the benefits of adding TZ to the AI ANA in postmenopausal women with advanced HER2+ and HR+ MBC. Both studies demonstrated statistically significant improvements in progression-free survival (PFS) with the addition of anti-HER2 therapy. Methods: An economic model was used to evaluate the incremental cost per quality-adjusted life year (QALY) gained with LET+LAP versus ANA+TZ as first-line treatment in postmenopausal women with HR+ and HER2+ MBC from the U.K. NHS perspective. Expected PFS and overall survival (OS) with LET+LAP and ANA+TZ were based on adjusted indirect comparison using data from the TAnDEM and EGF30008 trials as well as the P025 trial of LET versus tamoxifen (TAM) and the TARGET and North American trials of ANA versus TAM. Costs and utility values were obtained from the literature. Results: Shown in the Table (all results are discounted). LET+LAP yields more progression-free life years (PFLYs), life years (LYs), and QALYs than ANA+TZ. Medication costs are greater with LET+LAP, partly due to longer PFS. These higher costs are offset by savings in costs of drug administration. LAP+LET is therefore dominant (less costly and more QALYs) versus ANA+TZ. Conclusions: Letrozole plus lapatinib has greater effectiveness and lower cost from the U.K. NHS perspective when indirectly compared with anastrozole plus trastuzumab. Measure LET+LAP ANA+TZ Difference Effectiveness PFLY 1.181 1.042 0.139 LY 3.399 3.021 0.378 QALYs 2.434 2.162 0.272 Costs (in £) Medication 29,568 21,031 8,537 Drug administration 520 13,753 -13,232 Other preprogression 8,285 7,307 978 Other postprogression 20,105 17,943 2,162 Total 58,479 60,033 -1,554 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline, Royal Marsden NHS Foundation Trust & Institute of Cancer Research Research Fund

Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes.

Fulvestrant: Expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer

With the aromatase inhibitors (AIs) replacing tamoxifen as the first-line treatment for postmenopausal women with hormone receptor-positive early and advanced breast cancer, there is a need to evaluate appropriate endocrine treatment options following AI failure. However, until recently, there were no Phase III trial data in this area. Fulvestrant (Faslodex™) is an oestrogen receptor antagonist utilised for the treatment of postmenopausal women with locally advanced or metastatic breast cancer following progression or recurrence on anti-oestrogen therapy. Fulvestrant has a mode of action that is distinct from the AIs and the selective oestrogen receptor modulators, and thus may offer an effective treatment option in the post-AI setting. The Evaluation of Faslodex and Exemestane Clinical Trial (EFECT) is the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and the steroidal AI, exemestane, in patients with locally advanced or metastatic breast cancer who have progressed or recurred while receiving a non-steroidal AI. EFECT confirmed that fulvestrant and exemestane offer effective treatment options in this setting. Similar efficacy was seen in both treatment groups and there were no significant differences in reported adverse events between fulvestrant and exemestane. The EFECT data provide further evidence for the activity of fulvestrant in the treatment of advanced breast cancer. Other ongoing fulvestrant trials will further define its full role, including the potential for a high-dose regimen, combination of fulvestrant with an AI, and identification of clinical and biological markers to help in targeting those patients who are most likely to respond to treatment.

Metastatic breast cancer: sequencing hormonal therapy and positioning of fulvestrant

Fulvestrant, a novel estrogen receptor (ER) antagonist with no agonist effects, binds, blocks, and degrades the ER, thereby downregulating cellular ER levels, which in turn leads to reduced expression of the progesterone receptor. Due to this specific working mechanism, fulvestrant is an important addition to the armamentarium of endocrine agents in advanced breast cancer (ABC). Fulvestrant has been shown to be equally effective as the third-generation aromatase inhibitor (AI) anastrozole in postmenopausal patients with hormone-sensitive ABC progressing prior to tamoxifen. In another randomized phase III trial, it was shown that fulvestrant had similar efficacy to tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive ABC. When comparing the side effects of fulvestrant with tamoxifen and anastrozole, it was shown that fulvestrant is well tolerated compared with these agents and is associated with a lower incidence of joint disorders. Clinical benefit on fulvestrant treatment after AI therapy has been reported in a substantial number of patients (28-46%). On the other hand, it was also shown that sensitivity to further endocrine therapy is retained following progression on first-line or second-line fulvestrant (57% and 46% clinical benefit, respectively). In conclusion, fulvestrant provides us with an additional endocrine treatment option making it possible to prolong the time that patients with ABC can be treated with endocrine therapy.

Bisphosphonat (Risedronat) plus Kalzium in der Osteoporosetherapie — Ein Beitrag zu mehr Wirtschaftlichkeit? Eine Untersuchung aus gesundheitsökonomischer Sicht

Objective Osteoporosis is becoming increasingly important for the health care systems in developed western countries. National and international guidelines recommend bisphosphonates as first-line treatment for post-menopausal women to prevent hip fractures as a serious complication of osteoporosis. Additionally, a basic therapy with calcium and vitamin D is required which necessitates an appropriate supplementation with calcium. Therefore, it is important to evaluate the details of both cost and benefit potentials.

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.

Applicability of the intratumor aromatase preclinical model to predict clinical trial results with endocrine therapy.

Preclinical models and clinical studies have shown that aromatase inhibitors (AIs) are powerful inhibitors of estrogen synthesis and significantly suppress estrogen in vivo. For more than 20 years, standard first-line treatment for postmenopausal women with metastatic breast cancer has been the antiestrogen tamoxifen, a selective estrogen receptor modulator (SERM) with differential effects on breast, endometrial, bone, and vascular tissues. The estrogenic activity of tamoxifen is associated with deleterious clinical side effects, including vaginal bleeding, endometrial cancer, and thromboembolism. AIs are established second-line treatments in patients who progress with tamoxifen. Compared with progestins, such as megestrol acetate, or the earlier AIs aminoglutethimide and fadrozole, the new AIs, including exemestane, anastrozole, and letrozole, have increased efficacy and clinical benefit and cause fewer side effects in patients with metastatic breast cancer. Letrozole and anastrozole are approved first-line therapy for patients with metastatic breast cancer and as second-line treatment after tamoxifen failure. Studies in the intratumoral aromatase xenograft preclinical model have shown better responses with AIs than with antiestrogens in first-line therapy, and these data are consistent with the results from clinical trials. This model is now being used to assess whether combined or sequential administration of AIs with other agents may provide additional benefit.

The role of aromatase inhibitors in the treatment of metastatic breast cancer

Tamoxifen has been the gold standard of endocrine therapy for postmenopausal patients with hormone receptor-positive breast cancer for over 20 years. The development of the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane is changing the algorithm for the treatment of the disease. Recent clinical trials have shown that all three third-generation aromatase inhibitors present significant advantages over traditional progestins and aminoglutethimide therapy after tamoxifen failure in postmenopausal women. These new agents are now accepted as first choice for second-line treatment of metastatic disease. Since 2000, phase III trials with anastrozole and letrozole have shown that third-generation aromatase inhibitors are at least as effective as tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer. The first-line phase III trial of letrozole versus tamoxifen which, unlike the anastrozole trials, was prospectively designed to test superiority of the aromatase inhibitor, showed that this agent was superior to tamoxifen in all assessed outcome measures. A first-line phase III trial of exemestane versus tamoxifen in postmenopausal patients with hormone receptor-positive or -unknown advanced breast cancer is ongoing. The data presented in this article suggest that aromatase inhibitors may replace tamoxifen in the first-line hormonal management of this disease in postmenopausal women.

Anastrozole (Arimidex™) in clinical practice versus the old ‘gold standard’, tamoxifen

For the past 25 years, the estrogen antagonist tamoxifen has been considered the ‘gold standard’ for the treatment of breast cancer, despite certain tolerability issues and the risk of developing resistance. The aromatase inhibitors work by blocking the conversion of androgens to estrogen and were developed for use in patients where ovarian function had ceased (naturally, surgically or pharmacologically). Anastrozole, a third-generation nonsteroidal aromatase inhibitor that is a highly potent and selective inhibitor of the aromatase enzyme, has been shown to be superior to the gold standard tamoxifen for the first-line treatment of postmenopausal women with advanced breast cancer . As second-line therapy, anastrozole has shown superior survival compared with megestrol acetate and is also efficacious as neoadjuvant treatment in postmenopausal women and in combination with goserelin for the treatment of premenopausal women with advanced breast cancer. More recently, the results of the ATAC (anastrozole, tamoxifen, alone or in combination) trial, a large study in 9366 patients, demonstrated that anastrozole was significantly superior to tamoxifen for the treatment of postmenopausal women with early breast cancer, with regards to disease-free survival (p = 0.013) and incidence of contralateral breast cancer (p = 0.007). In addition, anastrozole was shown to be significantly better tolerated than tamoxifen with respect to endometrial cancer (p = 0.02), vaginal bleeding/discharge (p < 0.0001 for both), ischaemic cerebrovascular events (p = 0.0006), thromboembolic events (p = 0.0006) and hot flushes (p < 0.0001), while tamoxifen was associated with significantly less musculoskeletal disorders and fractures than anastrozole (p < 0.0001 for both). This review focuses on both the clinical pharmacology and the clinical data of anastrozole with emphasis on its future applications.