Mg In Postmenopausal Women Research Articles

OR01-5 Transition From Low Dose Denosumab 30mg to IV Zoledronic Acid: Effect on Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Prospective Observational Study

Abstract Introduction Cessation of denosumab(Dmab), a fully human monoclonal antibody to RANK-ligand, is associated with rises in bone remodelling, reductions in bone mineral density(BMD) and an increased fracture risk. We previously reported that BMD was stable following a switch from Dmab 60mg to 30mg in postmenopausal women with osteoporosis at a moderate fracture risk(1). The primary objective of this extension study is to evaluate the effect of switching patients from 30mg Dmab(6monthly) to IV Zoledronic acid (ZA), administered 6 months following the last dose of Dmab, in preventing bone loss in postmenopausal women with osteoporosis who are no longer at a high fracture risk. Methods Postmenopausal women with osteoporosis at a moderate or low fracture risk, previously on 30mg of Dmab 6monthly were switched to receive 5mg of IV ZA. Exclusion criteria included an additional skeletal disorder, prior fragility fracture, or use of oral steroids (daily in the past 12months). The primary endpoints were the mean percent change in BMD at the lumbar spine(LS), total hip(TH), femoral neck(FN) and 1/3radius(1/3R), as well as the percent change in alkaline phosphatase(ALP) at 24 months compared to baseline, following transition to IV ZA. Secondary outcomes were clinical fractures. Results 8 patients were included in the study. The mean duration of 30mg Dmab prior switching to IV ZA was 14.6 ± 2.8 months. Mean percent change in BMD at LS was -3.04(CI: 5.77, -0.32, p =0.033) and mean absolute change was -0.025gm/cm2(CI: -0.048, -0.002, p=0.038). The percent change at the TH was -2.64(CI: -4.97, -0.31, p=0.031) with a mean absolute change of -0.021 gm/cm2(CI: -0.040, -0.002, p=0.038). There were no statistically significant changes at the FN, or 1/3R sites at 24months post IV ZA. ALP showed 45.5% increase on average at 24months compared to baseline(95% CI: 14.1, 76.9, p=0.011). No clinical fractures were observed. Conclusions We observed a statistically significant decline in mean percent change in BMD at the LS and TH following a switch from 30mg Dmab to IV ZA at 24months following IV ZA administration. This is similar to the data seen following a switch from standard dose Dmab(60mg 6monthly) to IV ZA(2). The small decline in BMD seen maybe within the precision error of the assessment and this requires further evaluation in a larger number of patients. This was associated with a rise in ALP, however we did not observe any clinical fractures in this study.

Abstract OT1-01-07: PIONEER- Pre-operative wIndOw study of letrozole plus PR agonist megestrol acetate versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer

Abstract Background: Published preclinical findings provided new insights into the functional 'cross-talk' between the oestrogen receptor (ER) and the progesterone receptor (PR) in breast cancer (BC) (Mohammed et al., Nature, 2015). Addition of a PR agonist to anti-oestrogens directly modifies ERa chromatin binding and the transcriptional response in breast cancer cells, and is anti-proliferative in vitro and in vivo. Megestrol Acetate (MA), an off-patent semi-synthetic derivative of progesterone, has been licensed for many years as treatment for ER+ metastatic BC. There is also good evidence for the effectiveness of MA as a supportive therapy to ameliorate endocrine therapy-related hot flushes. Trial design: PIONEER is a three-arm, open label, multi-centre randomized phase II pre-surgical window trial evaluating effects of 15 days of preoperative therapy with Letrozole (LET), or LET plus MA 40mg, or LET plus MA 160mg in postmenopausal women with ER+ HER2- invasive primary BC. Eligibility criteria: Inclusion CriteriaPostmenopausal women with histologically confirmed invasive BC, ≥T1c, clinical NX or N0-N3, ER+ (Allred≥3), and HER2-2 groups of patients are potentially eligible: Cohort A: Patients whose cancers have been deemed to be operable by the Multi-Disciplinary Team (MDT) with surgery planned for the next 2-6 weeks Cohort B: Patients with early or locoregionally advanced BC planned for primary endocrine therapy either in lieu of surgery or as neoadjuvant therapy before surgery ECOG performance status of 0-2Adequate Liver, Renal, Bone marrow function Exclusion CriteriaHormone replacement therapy in the last 6 monthsTreatment with tamoxifen or an aromatase inhibitor (AI) in the last 6 monthsA progestogen-containing intrauterine system in situ, unless removed prior to randomisationMetastatic disease on presentationRecurrent BC (patients with a new primary invasive BC are eligible) Specific aims: The primary endpoint is % change in proliferation between baseline and day 15 tumor biopsies, measured by Ki67 IHC assessment. Secondary endpoints include: expression of Aurora Kinase A, Caspase 3 and AR/PR/EMT markers by IHC; and safety endpoints. Exploratory endpoints: transcription factor mapping (ChIP-seq) and identification of differential ERa-associated proteins (RIME) on paired fresh-frozen tumor samples. PIONEER will help determine whether there is value in conducting a Phase III adjuvant study to investigate the longer term benefit of combining an AI with MA, and if so, at what dose (40mg vs. 160mg). Statistical methods: Patients are randomized in a 1:1.5:1.5 ratio into arms A:B:C. Based on results from previous clinical trials, a mean 66% reduction in Ki67 is anticipated for LET alone (arm A), and a 77.5% reduction for the combination arms B and C, based on preclinical data. Present and target accrual: Patients are being recruited in Cambridge, Cornwall, Belfast & London with 6 other UK sites due to open q3/4 2018. At the time of submission, 29 patients had been recruited. A recruitment total of 189 patients is required. Citation Format: Kumar SS, Benson J, McIntosh S, King P, Dougall G, Kateb A, Vallier A-L, Jones L, Qian W, Provenzano E, Caldas C, Pantziarka P, Carroll J, Baird RD. PIONEER- Pre-operative wIndOw study of letrozole plus PR agonist megestrol acetate versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-07.

First-line vs second-line fulvestrant for hormone receptor-positive advanced breast cancer: A post-hoc analysis of the CONFIRM study

ObjectivesThe double-blind, phase III CONFIRM study (NCT00099437) evaluated fulvestrant 500 mg vs fulvestrant 250 mg in postmenopausal women with hormone receptor-positive locally advanced/metastatic breast cancer (LA/MBC). This post-hoc analysis investigated the efficacy and safety of fulvestrant given either first-line or second-line for advanced disease. Materials & methodsProgression-free survival (PFS) and overall survival (OS) with fulvestrant 500 mg vs fulvestrant 250 mg was evaluated using unadjusted log-rank tests in patients treated in the first- (progression during or within 12 months after completing adjuvant endocrine therapy; n = 387) and second-line (following endocrine therapy for LA/MBC; n = 343) settings. ResultsFirst-line fulvestrant 500 mg significantly prolonged PFS vs fulvestrant 250 mg (median PFS 5.6 vs 4.2 months; hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.64–1.00; p = .047). Median PFS was numerically greater with second-line fulvestrant 500 mg vs fulvestrant 250 mg (7.9 vs 6.3 months; HR 0.80; 95% CI 0.64–1.02; p = .068). At data cut-off (75.5% maturity), median OS with first-line fulvestrant 500 mg was 23.2 vs 22.1 months with fulvestrant 250 mg (HR 0.87; 95% CI 0.70–1.10; p = .251), and 29.2 vs 22.8 months, respectively, in the second-line (HR 0.75; 95% CI 0.58–0.96; p = .020). The safety profile was broadly comparable between dose groups and across treatment lines, and consistent with the overall patient population. ConclusionThe superiority of fulvestrant 500 mg over fulvestrant 250 mg in patients with LA/MBC in CONFIRM was consistent in both the first- and second-line settings for PFS, and numerically greater in both settings for OS.

Efficacy of fulvestrant in the treatment of postmenopausal women with endocrine-resistant advanced breast cancer in routine clinical practice.

This study aimed to describe the efficacy of fulvestrant 500mg in postmenopausal women with estrogen receptor (ER)-positive advanced/metastatic breast cancer who had disease progression after receiving anti-estrogen therapy in clinical practice, getting real-world data. Multicenter, retrospective, observational study conducted in Spain. Postmenopausal women with locally advanced/metastatic ER-positive breast cancer who received treatment with fulvestrant 500mg after progression with a previous anti-estrogen therapy were eligible. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), clinical benefit rate (CBR), duration of clinical benefit (DoCB), and safety profile. A total of 263 women were evaluated (median age, 65.8years). At a median follow-up of 21.5months, median PFS and OS were 10.6 and 43.2months, respectively. PFS according to 1st, 2nd, 3rd, and≥4th lines were 11.5, 10.6, 9.9, and 8.5months, respectively (p=0.0245). PFS in patients with visceral involvement was 10months vs 10.6months in patients without visceral involvement (p=0.6604), 9.6months in patients with high Ki67 vs 10months in patients with low Ki67 (p=0.7224), and 10.2months in HER2+patients vs 10.3months in HER2- patients (p=0.6809). The CBR was 56.5% and the DoCB was 18.4months. The most frequently adverse events were injection site pain (10.3%) and musculoskeletal disorders (7.6%). Fulvestrant 500mg administered in clinical practice was shown to be effective (PFS, 10.6months; CBR, 56.5%) and well tolerated, in accordance with previous trials.

264P - Patterns of treatment and outcome of fulvestrant 500mg in postmenopausal women with hormone-positive (HR+)/Her2-negative (HER2-) metastatic breast cancer (MBC): a real life multicenter Italian experience

264P - Patterns of treatment and outcome of fulvestrant 500mg in postmenopausal women with hormone-positive (HR+)/Her2-negative (HER2-) metastatic breast cancer (MBC): a real life multicenter Italian experience

F13 - Beyond clinical trials: a real life multicenter Italian experience on Fulvestrant 500mg in postmenopausal women with hormone-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC)

F13 - Beyond clinical trials: a real life multicenter Italian experience on Fulvestrant 500mg in postmenopausal women with hormone-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC)

Fulvestrant 500 mg vs 250 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer: a randomized, double-blind registrational trial in China.

The international CONFIRM study showed that fulvestrant 500 mg improved progression-free survival (PFS) vs fulvestrant 250 mg in postmenopausal women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer (LA/MBC). In this randomized, double-blind study, postmenopausal Chinese women with ER-positive LA/MBC and progression after endocrine therapy received fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or fulvestrant 250 mg (every 28 days). Consistency with the international study was assumed if the hazard ratio (HR) for comparison of PFS (primary endpoint) was < 1 (stratified log-rank test). The study was not powered to assess between-group differences.In total, 221 patients were randomized (fulvestrant 500 mg: n = 111; fulvestrant 250 mg: n = 110). Baseline characteristics were balanced. Median PFS was 8.0 months with fulvestrant 500 mg vs 4.0 months with 250 mg (HR = 0.75; 95% confidence interval [CI] 0.54−1.03; P = 0.078). PFS (HR; 95% CI) favored fulvestrant 500 mg in post-antiestrogen (0.86; 0.54−1.37) and post-aromatase inhibitor (0.65; 0.42−1.03) settings. No new safety considerations were observed. These results are consistent with the international CONFIRM study, supporting the superior clinical benefit of fulvestrant 500 mg in women with ER-positive LA/MBC experiencing progression following prior endocrine therapy.

Calcium supplements for the management of osteoporosis

It seems quite impossible that a worldwide accepted ‘dogma’ like the recommendation of calcium supplementation for the prevention of osteoporotic fractures is still debated in the most important medical journals. In fact it was about 30 years ago that the first consensus statement on osteoporosis recommended a daily calcium intake of 1500 mg in postmenopausal women [1], followed about 10 years later by the recommendation of vitamin D supplementation in older adults [2], although the latter was based on extrapolation of the results obtained in very old institutionalized women to the general population [3]. The recommended intake cannot easily be achieved through diet alone, and consequently middle-aged and older women worldwide are taking calcium plus vitamin D supplements. In fact, by the early 2000s, routine supplementation to reach at least 1200 mg calcium and 800 IU vitamin D daily was a common recommendation in medical practice for the prevention of osteoporotic fractures in women aged >50, supported also by the guidelines of different influential organizations, such as the US National Osteoporosis Foundation and the Europe-based International Osteoporosis Foundation. Thus the recent publication of two systematic reviews raising serious doubts about the efficacy of calcium intake from dietary sources or calcium supplements opened a heated debate on the matter. In the first paper, Tai and colleagues [4] reported a systematic review and meta-analysis of randomized controlled trials of dietary or supplemental calcium in women and men aged over 50: 15 trials studied dietary sources of calcium (n=1533) and 51 calcium supplements (n=12,257). Increasing calcium intake from dietary sources increased total hip and total body bone mineral density (BMD) by 0.6–1.0% , with no further gains beyond the first year. This limited improvement in BMD was similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus calcium+vitamin D, in trials with calcium doses of ≥1000 versus 500 mg/day, and in trials where the baseline dietary calcium intake was 1000 participants) randomized trials of calcium supplements, vitamin D supplements, or their combination, published to the end of 2010: • three reported a reduction in fracture risk, • nine reported no effect, and • two reported an increased fracture risk. Grey and Bolland also examined why calcium and vitamin D

Abstract P1-13-04: Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival

Abstract Background: Historically, androgens have been utilized for the treatment of breast cancer (BC) as the androgen receptor (AR) is the most highly expressed steroid receptor in BC (75-95% of estrogen receptor positive (ER+) and 50% of ER negative). Reports of the use of androgens in metastatic BC (MBC) indicate that women progressing on tamoxifen have the ability to respond to synthetic androgens with overall response rates in the range of 20-60%; however, these steroidal androgens also exhibit virilizing side effects, thus limiting clinical use. A non-steroidal, tissue-selective, AR modulator (SARM), such as enobosarm, offers a targeted approach of AR activation without virilization or estrogenic effects. Methods: This is a phase II proof of concept study examining the efficacy and safety of once daily enobosarm 9 mg in post-menopausal women with ER+ MBC who had responded to adjuvant and/or salvage endocrine therapy. Therapy is continued until patients display evidence of disease progression. The proportion of AR+ patients with clinical benefit response (CBR) at 6 months is the primary endpoint; defined as patients with a complete response (CR), partial response (PR), or stable disease (SD) as detailed in modified RECIST 1.1. AR status of metastatic disease will be correlated with CBR. Serum prostate specific antigen (PSA) will be assessed as a biomarker of AR activation by drug. Secondary endpoint is progression free survival (PFS). Results: Patient demographics: mean age 63.7 years, mean time from diagnosis 11.0 years, 72.7% prior chemotherapy, 89% (17/19) AR+. After a median follow-up of 81 days (range 7-304 days), preliminary results of 22 patients: 9 SD as best response, median duration 212 days. Current disposition of patients: 15 PD after a median 80 days (range 15-304 days), 4 SD (1 on treatment for &amp;lt; 6 months), and 3 early discontinuations (days 7, 28, 255). Five patients have died due to PD off study. Among the 17 evaluable patients, 6 reached the primary endpoint (35.3%; 95% CI=16.6% to 59.4%) with increased PSA, thereby exceeding the pre-defined statistical threshold requiring that at least 3 of 14 patients with an AR+ metastatic lesion demonstrate clinical benefit. CR or PR has not been observed. Current six month Kaplan-Meier estimate of PFS is 43.8% (95% confidence interval=19.5% to 68.1%). Enobosarm is well-tolerated with common grade 1/2 toxicities of nausea (8%), menopausal symptoms (13%), pain (25%), fatigue (10%), weight change (4%); 5 (4%) grade 3 toxicities (3 unrelated to drug, 1 bone pain, 1 fatigue), and no grade 4 or higher toxicities reported. Final results of the study will be available in the fourth quarter of 2014. Conclusions: Enobosarm demonstrates promise as a novel endocrine agent for AR+ MBC. The primary endpoint has been achieved, with 6/17 AR+ patients meeting statistical threshold for success (35% CBR at 6 months). Serum PSA appears to be a surrogate marker for AR activity associated with enobosarm administration. Based upon these favorable preliminary findings, a larger phase II study is anticipated. Citation Format: Beth Overmoyer, Pedro Sanz-Altimira, Ann H Partridge, Martine Extermann, Jane Liu, Eric Winer, Nancy Lin, Michael Hassett, Leroy Parker, Ryan Taylor, Michael Hancock, Susan Small, Mary Ann Johnston. Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-04.

Fulvestrant 250mg versus Anastrozole 1 mg in the Treatment of Advanced Breast Cancer: a Meta-Analysis of Randomized Controlled Trials

Most patients with advanced breast cancer experience resistance to endocrine treatment and eventual disease progression. This meta-analysis was designed to compare the efficacy and tolerability of fulvestrant 250 mg with anastrozole 1mg in postmenopausal women with advanced breast cancer. Electronic literature databases (Cochrane Library, Medline, and Embase) were searched for randomized controlled trials (RCTs) published prior to August 2013. Only RCTs that compared fulvestrant 250 mg to anastrozole 1mg in postmenopausal women with advanced breast cancer were selected. The main outcomes were time to treatment failure (TTF), time to progression (TTP), duration of response (DOR), clinical benefit rate, and tolerability. Four RCTs covering 1,226 patients (fulvestrant, n=621; anastrozole, n=605) were included in the meta-analysis. Fulvestrant increased the DOR compared to anastrozole (HR =1.31, 95% confidence interval [CI] 1.13-1.51). There was no statistically significant difference between fulvestrant and anastrozole in terms of TTF (HR=1.02, 95%CI 0.89-1.17), complete response (RR=1.79, 95%CI, 0.93-3.43), and partial response (RR=0.91, 95%CI 0.69-1.21). As for safety, there was no statistical significance between the two groups for common adverse events. Fulvestrant 250 mg is as effective and well-tolerated as anastrozole 1mg treatment for advanced breast cancer in postmenopausal women whose disease progressed after prior endocrine treatment. Thus, fulvestrant may serve as a reasonable alternative to anastrozole when resistance is experienced in breast cancer cases.

Comparative efficacy of everolimus versus fulvestrant for hormone-receptor–positive (HR+) advanced breast cancer (ABC) following progression/recurrence after first-line treatment: A network meta-analysis.

e11602 Background: Everolimus (EVE), an oral mammalian target of rapamycin (mTOR) inhibitor, is approved in combination with exemestane (EXE) to treat postmenopausal women (PMW) with HR+, human epidermal growth factor receptor-2–negative (HER2–) ABC that progressed after nonsteroidal aromatase inhibitor therapy. Fulvestrant (FUL), an estrogen receptor antagonist, is another treatment option for PMW previously treated with endocrine therapy. However, the comparative efficacy of EVE + EXE vs FUL is unknown. Methods: Six randomized, controlled trials in HR+, HER2–ABC patients were identified by systematic literature review (Cochrane library, National Horizon Scanning Centre, and NICE Web sites) that formed a network permitting indirect comparisons of EVE + EXE or EVE + tamoxifen (TAM) vs FUL: BOLERO-2, CONFIRM, EFECT, Paridaens (2008), SoFEA, and TAMRAD. All 6 trials had EXE, TAM, or FUL 250 mg as the common comparator to form the network. Relative efficacy of EVE and FUL was obtained using a Bayesian network meta-analysis based on these 6 trials. The primary endpoint was local assessment of progression-free survival (PFS) or time to progression (TTP). The hazard ratio (HR) of EVE + EXE relative to FUL and its 95% credible intervals (CrI) were calculated. Evidence of a difference between treatments is suggested by the 95% CrI not including 1. A HR &lt;1 indicates that the hazard rate is higher in the comparator group and that the treatment is more effective. Results: EVE + EXE was found to be more efficacious for PFS/TTP than FUL 250 mg (HR = 0.47; 95% Crl, 0.38-0.58) and more efficacious than FUL 500 mg (HR = 0.59; 95% Crl, 0.45-0.77). EVE + TAM was found to be numerically better for PFS/TTP than FUL 250 mg (HR = 0.65; 95% Crl, 0.40-1.04) and numerically better than FUL 500 mg (HR = 0.81; 95% Crl, 0.49-1.33). Conclusions: The indirect evidence from this analysis suggests that EVE in combination with EXE is more efficacious than FUL 250 and 500 mg in PMW with HR+, HER2– ABC that progresses after endocrine therapy. These data should be interpreted with caution as there is no randomized trial that directly compares EVE + EXE vs FUL.

CONFIRM Trial Final Analysis of Overall Survival: Fulvestrant 500 versus 250 mg

The Comparison of Fulvestrant 250 mg and 500 mg in Postmenopausal Women with Oestrogen Receptor Positive Advanced Breast Cancer Progressing or Relapsing After Previous Endocrine Therapy [CONFIRM] trial compared treatment with 2 doses of fulvestrant (250 vs 500 mg) in postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer that had recurred or progressed after endocrine therapy. The primary analysis showed that progression-free survival was significantly increased with fulvestrant 500 versus 250 mg [Di Leo A et al. J Clin Oncol 2010]. This article discusses the final analysis of overall survival.

Abstract S1-4: Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg

Abstract Background: The COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial (NCT00099437) compared fulvestrant 500 mg with fulvestrant 250 mg in postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer who had recurred or progressed following prior endocrine therapy. Fulvestrant 500 mg was associated with a statistically significant increase in progression-free survival compared with fulvestrant 250 mg (Di Leo A et al. J Clin Oncol 2010; 28: 4594–4600). At the time of the primary analysis approximately 50% of patients had died. Median overall survival was 25.1 months and 22.8 months for fulvestrant 500 mg and 250 mg, respectively (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.69, 1.03; p = 0.091). A follow-up analysis of overall survival was subsequently planned for when 75% of patients had died and the results are presented here. Methods: CONFIRM was a randomized, double-blind, parallel-group, multicenter, Phase III study. Patients were randomized 1:1 to either fulvestrant 500 mg (500 mg i.m. on Days 0, 14 and 28 and every 28 days thereafter) or fulvestrant 250 mg (250 mg i.m. every 28 days). After the primary analysis, patients on fulvestrant 250 mg were permitted to switch to 500 mg and all patients were followed up for overall survival, regardless of treatment discontinuation, unless consent was withdrawn. Overall survival was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) were also reported. Results: In total, 736 women (median age 61.0 years) were randomized between February 2005 and August 2007 from 128 centers in 17 countries (fulvestrant 500 mg: n=362; fulvestrant 250 mg: n=374). At time of follow-up analysis, 63 (9.0%) patients were lost to follow-up, 16 (2.2%) patients had withdrawn consent, 103 (14.0%) patients were still ongoing (21 [2.9%] on treatment and 82 [11.1%] not on treatment), and 554 (75.3%) patients had died. Eight (2.1%) patients crossed over from fulvestrant 250 mg to 500 mg. Median overall survival was 26.4 months for fulvestrant 500 mg and 22.3 months for fulvestrant 250 mg (HR 0.81; 95% CI, 0.69, 0.96; nominal p = 0.016). During the treatment period, a total of 32 (8.9%) patients had at least one SAE in the fulvestrant 500 mg and 25 (6.7%) patients in the fulvestrant 250 mg groups, and SAEs that were causally related to study treatment were reported for 6 (1.7%) and 3 (0.8%) patients, respectively. SAEs with an outcome of death were reported for 5 (1.4%) and 6 (1.6%) patients, respectively, during the treatment period. Overall, there were no clinically important differences in the profiles of SAEs between the treatment groups and no clustering of SAEs could be detected in either treatment group. Conclusions: Overall survival data from CONFIRM demonstrate that, in patients with locally advanced or metastatic ER positive breast cancer, fulvestrant 500 mg is associated with a clinically relevant 4.1 month difference in median overall survival and 19% reduction in risk of death compared with fulvestrant 250 mg. There were no new safety concerns associated with the use of fulvestrant 500 mg. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-4.

Cost-effectiveness of fulvestrant 250 mg versus 500 mg in postmenopausal women with estrogen receptor-positive metastatic breast cancer and disease progression after antiestrogen therapy

To determine the cost-effectiveness of fulvestrant 250 mg compared to 500 mg in postmenopausal women with estrogen receptor-positive metastatic breast cancer and disease progression after antiestrogen therapy. A Markov model was constructed to find the incremental cost-effectiveness of fulvestrant 250 mg monthly when compared with the 500 mg monthly in patients with progression after antiestrogen therapy. The model duration was 24 months. Clinical efficacy data inputs were derived from a phase III clinical trial demonstrating a statistically significant increase in progression-free survival in patients receiving 500 mg versus 250 mg. Cost data utilized were all relevant Ambulatory Payment Classification payment rates from the 2011 Medicare Outpatient Prospective Payment System. A Monte Carlo simulation was performed to test the model at various willingness to pay thresholds. The incremental cost-effectiveness ratio as determined by the Markov model was US$10,972 per month of progression-free survival for the 500 mg dose compared with the 250 mg dose. Using a Monte Carlo simulation, it was found that 500 mg monthly was cost-effective at and above the willingness to pay threshold of US$15,000 per month. A series of one-way sensitivity analyses showed this result is robust to geographical practice variations in costs of drug administration and physician examination. From a third party payer perspective, the value of fulvestrant 500 mg monthly is dependent on the willingness to pay threshold. Despite a labeling change for fulvestrant in September 2010, fulvestrant 250 mg monthly appears to be a viable option in the target population.

Validation of a calcium assessment tool in postmenopausal Canadian women

Adequate calcium intake is important for optimal bone health. Assessing dietary calcium intake, however, is neither widely done nor standardized in North American clinical practices. Objective Our goal was to validate a calcium assessment tool (CAT), a modified version of the Calcium Calculator™, against the 3-day food record. Methods Data were obtained from 348 participants in the ECKO (Evaluation of the Clinical use of vitamin K supplementation in postmenopausal women with Osteopenia) trial. In this study, CAT data was collected at baseline and 3-day food records (FRs) were collected at baseline and 3 months by trained study coordinators. CAT and 3-day FR data were compared using correlations and Bland–Altman plots. Additionally, receiver operator characteristic (ROC) curves of CAT were constructed to identify subjects with low calcium intake at thresholds of 500 mg/day and 1000 mg/day on the 3-day FR curves. Results Mean calcium intake values per day were 902 mg for the 3-day FRs and 781 mg for the CAT. The Pearson correlation was 0.57 (95% CI: 0.50–0.64). Areas under the ROC curves at thresholds of 500 and 1000 mg calcium were 0.81 (95% CI: 0.73–0.89) and 0.82 (95% CI: 0.78–0.86), respectively. Conclusions The CAT is a valid tool for the measurement of dietary calcium intake using cut-off values of 500 mg and 1000 mg in postmenopausal women, even though there is only moderate correlation between the CAT and 3-day FR. This tool may facilitate the determination of whether calcium supplements are needed in the clinical setting.

Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer

We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy. Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. Patients were randomly assigned to fulvestrant 500 mg (500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) or 250 mg every 28 days. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, clinical benefit rate (CBR), duration of clinical benefit (DoCB), overall survival (OS), and quality of life (QOL). PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006), corresponding to a 20% reduction in risk of progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%, respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS were 16.6 and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg.

CONFIRM: A Phase III, Randomized, Parallel-Group Trial Comparing Fulvestrant 250 mg vs Fulvestrant 500 mg in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer.

Abstract Background: Fulvestrant (Faslodex®) is an estrogen-receptor (ER) antagonist licensed for the treatment of postmenopausal women with advanced breast cancer who have progressed or recurred following prior endocrine therapy. The efficacy of fulvestrant at the approved dose (250 mg/month; F250) is well established; however, increasing the dose to 500 mg (500 mg i.m. on Day 0, then 500 mg i.m. on Days 14 and 28 and every 28 days thereafter; F500) may further improve clinical outcome. Data from the NEWEST and FIRST studies have suggested improved biological and clinical activity for F500 in the neoadjuvant and 1st-line advanced disease settings respectively. Further data are required to clarify the clinical role of F500 in ER+ advanced breast cancer.Methods: CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) is a randomized, double-blind, parallel-group, multicenter, Phase III study (9238IL/0064; NCT00099437) comparing F250 with F500 in postmenopausal women with ER+ advanced disease recurring or progressing after prior endocrine therapy (anti-estrogen or aromatase inhibitor). Eligible patients (pts) were randomized 1:1 to F250 or F500, and assessed for tumor progression every 12 weeks. The primary objective was to compare the efficacy of F250 and F500 in terms of time to progression (TTP). Secondary objectives included: objective response rate (ORR), clinical benefit rate (CBR; complete or partial response or stable disease lasting ≥24 weeks), duration of clinical benefit (DoCB)(all by modified RECIST criteria), overall survival and quality of life (QoL). Safety and tolerability were also assessed. Treatment with fulvestrant continued until disease progression, or discontinuation for any other reason. All patients were followed up for disease progression and survival, regardless of treatment discontinuation, unless consent was withdrawn.Results: In total, 736 women (median age 61.0yrs) were recruited between Feb '05 and Aug '07 from 128 centers in 17 countries (F500: n=362; F250: n=374). TTP was significantly longer for F500 vs F250 (HR 0.80 [95% CI: 0.68, 0.94]; p=0.006), corresponding to a 20% reduction in risk of progression. The treatment effect was consistent for all predefined subgroups analysed. ORR was similar for F500 and F250 (13.8% vs 14.6%; odds ratio 0.94 [95% CI 0.57, 1.55]; p=0.795). There was a numerical advantage in CBR for pts receiving F500 vs F250 (45.6% vs 39.6%; odds ratio 1.28 [95% CI 0.95, 1.71]; p=0.1) and in DoCB (16.6 vs 13.9 months for F500 [n=165] and F250 [n=148] respectively). There was a trend for improved overall survival for pts treated with F500 compared with F250 (HR 0.84 [95% CI: 0.69, 1.03] p=0.091). QoL (n=145) was similar for both arms. F500 was well tolerated, with a safety profile consistent with that of F250 and no evidence of dose-dependence for any AE.Discussion: The CONFIRM trial has shown a statistically significant increase in TTP for F500 compared with F250, without increase in toxicity. This translates into a clinically meaningful advantage for F500 over F250. We anticipate that the 500mg regimen will become the established dose for fulvestrant. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 25.

DXA-based hip structural analysis of once-weekly bisphosphonate-treated postmenopausal women with low bone mass

DXA-based hip structural analysis from 947 individuals completing two large osteoporosis clinical trials was pooled and analyzed. Treatment with once-weekly (OW) ALN or OW RIS resulted in significant improvements from baseline in geometric parameters at all three HSA ROIs. Improvements were generally greater with OW ALN than OW RIS. BMD can be altered by changes in distribution and quantity of bone and changes in mineralization. These effects cannot be distinguished with conventional measurements of BMD. Currently, tissue composition is evaluated only by invasive means. Structural geometry of the proximal femur, however, can be measured in vivo by several methods, including dual energy X-ray absorptiometry (DXA) using specialized hip structure analysis (HSA) software. DXA-based HSA was obtained and analyzed in a subset of 947 subjects participating in the Fosamax Actonel Comparison Trials. Data were pooled to evaluate treatment effects on the structural geometry of the proximal femur by once-weekly alendronate (ALN) 70 mg and risedronate (RIS) 35 mg in postmenopausal women with low bone mass. Both ALN and RIS treatment over 2 years resulted in improvements in HSA-derived geometry at all three HSA regions of interest (ROI). The largest treatment effects were seen at the intertrochanteric ROI. Consistently greater treatment effects were seen with ALN compared with RIS at all three HSA-ROIs. HSA offers insight into the potential mechanisms of fracture risk reduction from pharmacologic intervention. In the current study, treatment with once-weekly bisphosphonates resulted in significant improvements in hip geometric parameters.

NEWEST: a Phase II, randomised, neoadjuvant trial comparing fulvestrant 500 mg vs 250 mg in postmenopausal women with locally advanced, oestrogen receptor-positive (ER+) breast cancer

NEWEST: a Phase II, randomised, neoadjuvant trial comparing fulvestrant 500 mg vs 250 mg in postmenopausal women with locally advanced, oestrogen receptor-positive (ER+) breast cancer

Effect of once-yearly infusion of zoledronic acid 5 mg in postmenopausal women with osteoporosis

A general rule of strength and plasticity was proposed for three typical wrought Al alloys (2xxx, 6xxx, and 7xxx) subjected to different aging times. Investigations of the work-hardening processes and dislocation configurations in tensile and compressive testing reveal that this general rule arises because there is a common mechanism for these three kinds of wrought alloys whereby the tendency for cross-slip increases monotonously with aging time. By analyzing the strain hardening exponent and the stacking fault energy, it is demonstrated that the change in the dislocation slip mode is attributed mainly to the formation of second phases rather than to the matrix composition. Accordingly, a new work-hardening model was proposed for wrought Al alloys containing second phases and this explains the interaction between dislocations and second phases and other relevant experimental phenomena. This work is therefore beneficial for quantitatively investigating and optimizing the strength and plasticity of wrought aluminum alloys.