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Hormonal therapy plays a vital part in the treatment of estrogen receptor–positive (ER +) breast cancer. ER can be activated in a ligand-dependent and independent manner. Currently available ER-targeting agents include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). Estrogen receptor mutation (ESR1 mutation) is one of the common mechanisms by which breast cancer becomes resistant to additional therapies from SERMs or AIs. These tumors remain sensitive to SERDs such as fulvestrant. Fulvestrant is limited in clinical utilization by its intramuscular formulation and once-monthly injection in large volumes. Oral SERDs are being rapidly developed to replace fulvestrant with the potential of higher efficacy and lower toxicities. Elacestrant is the first oral SERD that went through a randomized phase III trial showing increased efficacy, especially in tumors bearing ESR1 mutation, and good tolerability. Two other oral SERDs recently failed to achieve the primary endpoints of longer progression-free survival (PFS). They targeted tumors previously treated with several lines of prior therapies untested for ESR1 mutation. Initial clinical trial data demonstrated that tumors without the ESR1 mutation are less likely to benefit from the SERDs and may still respond to SERMs or AIs, including tumors previously exposed to hormonal therapy. Testing for ESR1 mutation in ongoing clinical trials and in hormonal therapy for breast cancer is highly recommended. Novel protein degradation technologies such as proteolysis-targeting chimera (PROTACS), molecular glue degrader (MGD), and lysosome-targeting chimeras (LYTACS) may result in more efficient ER degradation, while ribonuclease-targeting chimeras (RIBOTAC) and small interfering RNA (siRNA) may inhibit the production of ER protein.

Women between 59 and 80 years of age with a bone mineral density T score of –2.5 or less at the femoral neck or spine received the selective estrogen-receptor modulator lasofoxifene (either 0.25 or 0.5 mg daily) or placebo for 5 years. Lasofoxifene was associated with lower risks of fractures, estrogen-receptor–positive breast cancer, coronary heart disease, and stroke, with no increase in endometrial cancer, but there was an increase in venous thromboembolic events. In women with osteoporosis, lasofoxifene was associated with lower risks of fractures, estrogen-receptor–positive breast cancer, coronary heart disease, and stroke, with no increase in endometrial cancer, but there was an increase in venous thromboembolic events. Lasofoxifene is a nonsteroidal selective estrogen-receptor modulator that decreases bone resorption, bone loss, and low-density- lipoprotein (LDL) cholesterol in postmenopausal women. 1 We conducted the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial to determine whether lasofoxifene would reduce the risk of fractures, estrogen receptor (ER)–positive breast cancer, and cardiovascular disease among postmenopausal women with osteoporosis. Methods Study Design The PEARL trial was an international, randomized, placebo-controlled trial. Subjects received 1 g of calcium and 400 to 800 IU of vitamin D and placebo during a 6- to 8-week run-in period; women who received 75% or more of these pills were . . .

Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2–3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. After a median follow-up of 55·7 months (range 0–89·7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0·76 (95% CI 0·66–0·88, p=0·0001) in favour of exemestane, absolute benefit 3·3% (95% CI 1·6–4·9) by end of treatment (ie, 2·5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0·85 (95% CI 0·71–1·02, p=0·08), 0·83 (0·69–1·00, p=0·05) when 122 patients with oestrogen-receptor-negative disease were excluded. Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2–3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

In this multicenter, placebo-controlled, randomized trial of postmenopausal women at high risk for a coronary event, raloxifene had no significant effect on the risk of primary coronary events, reduced the risk of invasive breast cancer and vertebral fractures, and increased the risk of fatal stroke and venous thromboembolism. A decision whether to use raloxifene for the prevention of breast cancer or vertebral fractures should be individualized, weighing benefits against potential risks. In postmenopausal women at high risk for a coronary event, raloxifene had no significant effect on the risk of primary coronary events, reduced the risk of invasive breast cancer and vertebral fractures, and increased the risk of fatal stroke and venous thromboembolism. Raloxifene is a nonsteroidal selective estrogen-receptor modulator (SERM) that binds to the estrogen receptor, leading to estrogen-agonist effects in some tissues and estrogen-antagonist effects in others. 1 Raloxifene therapy has been associated with improvement in the levels of serum lipoprotein cholesterol, 2 , 3 fibrinogen, 3 and homocysteine. 4 The favorable effect of raloxifene on markers of cardiovascular risk, coupled with evidence from observational studies that treatment with estrogen was associated with a reduced risk of coronary heart disease (CHD) in postmenopausal women, 5 , 6 led to the design of the Raloxifene Use for The Heart (RUTH) trial to determine the effect of raloxifene on clinical . . .

The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.

Low testosterone (T) levels are often found in obese men with impaired glucose tolerance (IGT) and overt type 2 diabetes (T2DM); however, the mechanisms underlying this condition and its correct therapy are still under debate. To evaluate the effectiveness of clomiphene citrate (CC) in increasing endogenous T levels in obese men with low serum T and with IGT or T2DM treated with metformin (MET). Cross-over, randomized, double-blind, placebo-controlled study. 24 obese men, aged 47.3 ±. 6.3 (range 35-55 years), with low T level (≤3 ng/mL) and naïve diagnosis of IGT or T2DM were included. Subjects were randomized to CC 25 mg/day or placebo (Plac) with MET 2 g/day for 3 months. After a 6-week wash-out period, subjects were moved to the alternative arm for additional 3 months. Clinical evaluation and blood exams performed prior to and at the end of treatment. Of 24 randomized, 21 were evaluable, classified as IGT (n = 11) or T2DM (n = 10). Compared to baseline levels, T levels increased significantly after 3 months of CC treatment (3.03±0.80 to 5.99±1.67 ng/mL P<0.001) but not after the Plac treatment (2.87±0.78 to 3.09±0.84 ng/mL P<0.001 between the treatments). T changes were similar in IGT and T2DM subjects. Gonadotropins as well raised significantly after CC treatment (LH 3.83±1.45 to 8.53±6.40 mU/mL; FSH 4.84±1.67 to 10.15±5.08 mU/mL P<0.001 respectively), whereas no changes for LH (3.51±1.59 to 3.63±1.39 mU/mL) but a smooth increased for FSH (4.61±2.49 to 5.39±2.65 mU/mL; P = 0.004) were shown after Plac treatment (LH P = 0.001 and FSH P = 0.002 between treatments). Furthermore, fasting glucose (106.8±23.2 to 101.1±25.7 mg/dL; P = 0.004), insulin (19.3±12.1 to 15.6±10.1 μU/mL; P = 0.010) and HOMA-IR (4.94±2.89 to 3.69±2.12; P = 0.001) decreased significantly during the CC treatment period, whereas no significant changes were observed in any of these parameters in the Plac treatment. A low dose of CC therapy was able to significantly increase serum T levels in all participants with mild modifications of clinical and metabolic parameters. EudraCT 2011-000439-10.

Summary In this 2-year extension of a 3-year study, bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated. Introduction This study evaluated the efficacy and safety of bazedoxifene for the treatment of postmenopausal osteoporosis over 5 years. Methods A total of 4,216 postmenopausal women with osteoporosis were enrolled in this 2-year extension of a 3-year, randomized, double-blind, placebo-controlled, phase 3 trial. In the core study ( N  = 7,492), subjects received bazedoxifene 20 or 40 mg/day, raloxifene 60 mg/day, or placebo. The raloxifene arm was discontinued after 3 years; subjects receiving bazedoxifene 40 mg were transitioned to bazedoxifene 20 mg after 4 years. Five-year findings are reported for bazedoxifene 20 and 40/20 mg and placebo. Endpoints included incidence of new vertebral fractures (primary) and non-vertebral fractures, and changes in bone mineral density (BMD) and bone turnover markers. Results At 5 years, the incidence of new vertebral fractures in the intent-to-treat population was significantly lower with bazedoxifene 20 mg (4.5%) and 40/20 mg (3.9%) versus placebo (6.8%; P  < 0.05), with relative risk reductions of 35% and 40%, respectively. Non-vertebral fracture incidence was similar among groups. In a subgroup of higher-risk women ( n  = 1,324; femoral neck T-score ≤−3.0 and/or ≥1 moderate or severe or ≥2 mild vertebral fracture[s]), bazedoxifene 20 mg reduced non-vertebral fracture risk versus placebo (37%; P  = 0.06); combined data for bazedoxifene 20 and 40/20 mg reached statistical significance (34% reduction; P  < 0.05). Bazedoxifene significantly increased BMD and reduced bone turnover versus placebo ( P  < 0.05) and was generally safe and well tolerated. Conclusions The findings support a sustained anti-fracture effect of bazedoxifene on new vertebral fractures in postmenopausal osteoporotic women and on non-vertebral fractures in the higher-risk subgroup of women.

Summary Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. Introduction We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. Methods In the core study, healthy postmenopausal women with osteoporosis (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. Results A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. Conclusion Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years.

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

Acquired resistance occurs in metastatic hormone receptor–positive breast cancer patients. The addition of interferon beta/interleukin-2 immunotherapy to first-line salvage hormone therapy (HT) prolonged progression-free (PFS) and overall survivals (OS) in 26 patients, as compared with 30 historical controls and literature data. This was a 2 : 1 ratio case–control retrospective observational study. The cases were from an open pilot study, started in 1992, and controls were recruited in 2006. The planned mean follow-up time was the time at which more than 80% of controls progressed. The median PFS was significantly longer in the cases than that in controls, 33.1 (95% CI 24.5–41.8) vs 18 (95% CI 12.1–23.8) months (p < 0.0001). Also, median OS was significantly longer in the cases, 81 vs 62 (95% CI 48.1–75.9) months (p < 0.0029). When analysis of the 2 groups was adjusted for the disease-free interval (DFI), hormone receptor status, HER2, site of metastases and molecular-targeted therapies, the hazard ratio for PFS and for OS in the cases increased from 2.347 to 3.090 and from 1.874 to 2.147, respectively. This occurred in spite of the higher proportion of controls (82% vs 7.1%) treated with aromatase inhibitors (AIs), while selective oestrogen receptor modulators (SERMs) were given to 92.9% of the cases and to 18% of the control group (p < 0.0001). Immunotherapy significantly prolonged PFS and OS during conventional first-line HT. A multi-centre randomised clinical trial is advised to enter this immunotherapy into clinical practice.Key messages• Acquired resistance occurs in metastatic endocrine-dependent breast cancer patients.• Interferon beta-interleukin-2 immunotherapy added to first-line salvage hormone therapy prolonged progression-free (PFS) and overall (OS) survivals in 26 patients of a pilot study as compared with 30 historical controls.• In this 2:1 ratio case–control prospective observational study, the PFS median time was significantly longer in the study group than that in controls, 33.1 (95% CI 24.5–41.8) vs 18 (95% CI 12.1–23.8) months (p < 0.0001).• Also, the OS median time was significantly longer in the study group, 81 vs 62 (95% CI 48.1–75.9) months (p < 0.0029).