Treatment Of Postmenopausal Women Research Articles

Abstract PD2-06: Inhibition of 3-phosphoinositide dependent protein kinase 1 (PDK1) synergizes with CDK4/6 inhibitors against ER-positive breast cancer

Abstract Background: Dysregulation in cell cycle checkpoints is common in cancer. Small molecule inhibitors that target the CDK4/6/cyclinD1 pathway of the cell cycle are in clinical development. Recently the combination of the CDK4/6 inhibitor palbociclib and the aromatase inhibitor letrozole was approved for the treatment of post-menopausal women with ER+/HER2- advanced breast cancer. However, not all patients benefit from CDK4/6 inhibitors and a significant fraction of them eventually progress on these agents, underscoring the need to develop potent therapeutic strategies to circumvent drug resistance. Methods: We performed a high-throughput RNA interference (RNAi) kinome screen targeting 720 kinases to identify targetable molecules whose inhibition, in combination with the CDK4/6 inhibitor LEE011 (ribociclib), induced synthetic lethality in MCF7 ER+ breast cancer cells. PDK1 RNAi oligonucleotides and the PDK1 inhibitor GSK2334470 in combination with each of the CDK4/6 inhibitors, palbociclib and LEE011, were tested against ER+ breast cancer cells. In vivo anti-tumor efficacy of LEE011 and GSK2334470 was assessed in ovariectomized athymic nude mice bearing MCF7 xenografts. Results: A siRNA kinome screen identified PDK1 as the top RNA whose downregulation sensitized MCF7 cells to CDK4/6 inhibitors. This was confirmed with independent siRNAs in ER+ MCF7, T47D, HCC1428 and HCC1500 breast cancer cells. Pharmacological inhibition of PDK1 with the ATP-competitive, small molecule inhibitor GSK2334470 in combination with each of the CDK4/6 inhibitors, LEE011 and palbociclib, synergistically inhibited proliferation and increased apoptosis of MCF7 and T47D cells (combination index 0.19-0.89). LEE011-resistant MCF7 and T47D cells were generated by chronic treatment with doses of LEE011 up to 1 µM. Drug-resistant cells displayed increased levels of PDK1, phosphorylated Rb, and phosphorylated S6 ribosomal protein (pS6), an effector of the PDK1 substrate p70S6K, compared to parental drug-sensitive cells. Inhibition of PDK1 with siRNA or GSK2334470 re-sensitized the LEE011-resistant cells to the CDK4/6 inhibitors. Genetic (RNAi) and pharmacological inhibition of PDK1 (with GSK2334470) abrogated pS6 levels whereas inhibition of AKT with the small molecule inhibitor MK2206 did not affect pS6 levels, suggesting PDK1 can induce resistance to CDK4/6 inhibitors via p70S6K/pS6 signaling in an AKT-independent manner. The effects observed in cell lines in culture were recapitulated in vivo using MCF7 xenografts established in ovariectomized nude mice in the absence of estrogen supplementation. Treatment with GSK2334470 and LEE011 induced tumor regressions (8/8 tumors by RECIST criteria) more potently than either drug alone. Conclusions: These data support a critical role of PDK1 in mediating acquired resistance to CDK4/6 inhibitors in ER+ breast cancer cells. Co-targeting of the PDK1 and CDK4/6 pathways may overcome resistance to CDK4/6 inhibitors and is worthy of further translational and clinical investigation in patients with ER+ breast cancer. Citation Format: Jansen VM, Bhola NE, Bauer JA, Formisano L, Moore P, Koch J, Arteaga CL. Inhibition of 3-phosphoinositide dependent protein kinase 1 (PDK1) synergizes with CDK4/6 inhibitors against ER-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD2-06.

Comparison of the effects of eldecalcitol with either raloxifene or bisphosphonate on serum tartrate resistant acid phosphatase-5b, a bone resorption marker, in postmenopausal osteoporosis.

This study analyzes whether concomitant raloxifene (RLX) or bisphosphonates (BP) plus eldecalcitol (ELD) has excessive suppressive effects on a bone resorption marker during the first 6 months of treatment in postmenopausal women in real-world setting. 285 postmenopausal osteoporotic patients who had been treated with RLX or BP plus ELD were evaluated the bone resorption marker, serum tartrate resistant acid phosphatase-5b (TRACP-5b), during the first 6 months of treatment. In drug-naïve group (not received osteoporosis medications before the administration, n=70), the concomitant RLX or BP with ELD significantly decreased levels of TRACP-5b without severe suppression. In vitamin D switch group [RLX or BP plus alfacalcidol (ALF) and then switched to RLX or BP plus ELD, n=215], the replacing ALF with ELD further and significantly decreased TRACP-5b and tertile analyses based on baseline values were significantly decreased far more in the highest, compared with the lowest tertile in the ELD+RLX and ELD+BP groups. ELD combined with RLX or BP administered for 6 months to postmenopausal women with osteoporosis who were drug-naïve or who had switched medications significantly reduced and maintained TRACP-5b values within the reference range.

Therapeutic Place of Fulvestrant in the Management of Hormone-receptor Positive Breast Cancer

Fulvestrant is an oestrogen-receptor antagonist that exerts selective oestrogen receptor downregulation, antiproliferative activity and induction of apoptosis. It is indicated for the treatment of postmenopausal women with locally advanced or metastatic breast cancer for disease relapse or progression on or after adjuvant anti-oestrogen therapy. Fulvestrant was initially approved at a dose of 250 mg, however, the results of the CONFIRM trial led to approval of 500 mg dose (i.e. 500 mg on days 0, 14 and 28, then 500 mg every 28 days). Fulvestrant has also shown superiority over anastrozole as first-line therapy in the phase II trial. There are contrasting data for its efficacy when used in combination with anastrozole. It is well tolerated, with no significant difference with respect to the toxicity profile of other hormonal therapies. Treatment with fulvestrant is not associated with any clinically significant effects on sex hormone levels, bone-specific turnover markers or endometrial thickening. Fulvestrant has been recommended by the National Comprehensive Cancer Network and the European School of Oncology guidelines as a treatment option in first- and second-line management of hormone-receptor positive breast cancer.

Abstract A43: RB pathway disruption by the CDK4/6 inhibitor palbociclib enhances responses to chemotherapy in squamous cell lung cancer

Abstract Lung cancer remains one of the leading causes of cancer-related mortality. Squamous cell lung cancer (SqCLC) is the second most common subtype of non-small cell lung cancer (NSCLC). Despite recent development of effective targeted therapeutic agents for lung adenocarcinoma, patients with SqCLC often receive conventional cytotoxic chemotherapy as this cancer subtype lacks genomic alterations that can be targeted by personalized medicine. Hence, novel approaches that enhance the efficacy of chemotherapy will benefit treatment outcomes in this patient population. CDK inhibitors comprise a class of drugs that targets the dysregulated cell cycle in malignant cells. Treatment of tumor cells with the CDK4/6 inhibitor palbociclib inhibits tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Based on promising clinical trial data, palbociclib in combination with letrozole was granted accelerated approval by the US FDA for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer. In this preclinical study, we explored the effect of palbociclib on several chemotherapies (taxanes, platins, and antimetabolites) in preclinical models of SqCLC. Because the activity of chemotherapy generally requires cell cycle progression, careful combination/sequencing of this class of drugs with CDK inhibitors may be important to achieve synergy as well as avoid potential antagonism. To obtain optimal activity of palbociclib and chemotherapy combinations, we investigated several combination/sequencing regimens (concurrent, chemotherapy followed by palbociclib or the reverse sequence) in several SqCLC cell lines. We did not encounter antagonism of chemotherapy-mediated cytotoxicity by palbociclib in any of the tested regimens. Rather, we observed robust combinatorial anti-cancer cell activity in all settings. Combination of palbociclib with chemotherapy was associated with reduction of RB phosphorylation and FOXM1 protein levels, and the induction of p21. Our studies demonstrated that, while palbociclib partially antagonized chemotherapy-induced apoptosis, it significantly synergized with chemotherapy to induce cell cycle arrest as well as a senescence-like phenotype. Cells pretreated with palbociclib plus cisplatin or palbociclib plus docetaxel displayed less cell growth upon drug removal compared to those treated with monotherapies. Finally, palbociclib treatment that followed docetaxel, nab-paclitaxel or cisplatin treatment significantly enhanced the antitumor activity of the chemotherapies in several cell line-derived or patient-derived xenograft models. Our results suggest that treatment with optimal palbociclib and chemotherapy combination/sequencing could lead to better clinical outcomes for SqCLC patients. Citation Format: Ping Wei, Joan Cao, Goldie Lui, Hui Wang, Konstantinos Tsaparikos, David Shields, Kim Arndt, Paul Rejto, Todd VanArsdale, James Hardwick. RB pathway disruption by the CDK4/6 inhibitor palbociclib enhances responses to chemotherapy in squamous cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A43.

Reduced fat mass and increased lean mass in response to 1 year of melatonin treatment in postmenopausal women: A randomized placebo-controlled trial.

Apart from regulating the circadian rhythm, melatonin exerts a variety of actions in the living organism. Among these functions, melatonin is believed to have a positive effect on body weight and energy metabolism. So far, the evidence for this relies mainly on animal models. In this study, we aimed to determine the effects of melatonin on body composition, lipid and glucose metabolism in humans. In a double-blind, placebo-controlled study, we randomized 81 postmenopausal women to 1 year of treatment with melatonin (1 or 3 mg nightly) or placebo. Body composition was measured by DXA. Measures were obtained at baseline and after 1 year of treatment along with leptin, adiponectin and insulin. Markers of glucose homeostasis were measured at the end of the study. In response to treatment, fat mass decreased in the melatonin group by 6·9% (95% CI: 1·4%; 12·4%, P = 0·02) compared to placebo. A borderline significant increase in lean mass of 5·2% was found in the melatonin group compared to placebo (3·3%, (IQR:-1·7; 6·2) vs -1·9%, (IQR: -5·7; 5·8), P = 0·08). After adjusting for BMI, lean mass increased by 2·6% (95% CI: 0·1; 5·0, P = 0·04) in the melatonin group. Changes in body weight and BMI did not differ between groups. Adiponectin increased borderline significantly by 21% in the melatonin group compared to placebo (P = 0·08). No significant changes were observed for leptin, insulin or markers of glucose homeostasis. Our results suggest a possibly beneficial effect of melatonin on body composition and lipid metabolism as 1 year of treatment reduces fat mass, increases lean mass and is associated with a trend towards an increase in adiponectin.

Overuse and Underuse of Antiosteoporotic Treatments According to Highly Influential Osteoporosis Guidelines: A Population-Based Cross-Sectional Study in Spain.

Inappropriate prescribing of antiosteoporotic medications has been observed; however, the joint study of both overuse and underuse has barely been attempted. Spain, with its high utilization rates, constitutes a good example to assess differences in over and under use according to diverse highly-influential osteoporosis guidelines (HIOG) worldwide. We used data of a population-based cross-sectional study including 824 post-menopausal women ≥50 years old living in the city of Valencia, Spain and aimed to estimate the percentage of women eligible for treatment, and the proportion of overuse and underuse of antiosteoporotic treatment according to HIOG. The prevalence of antiosteoporotic treatment in postmenopausal women ≥ 50 in Valencia was 20.9% (95%CI:17.6–24.4). The type of antiosteoporotic drugs prescribed varied greatly depending on the medical specialty responsible of the initial prescription. When applying the HIOG, the percentage of women 50 and over who should be treated varied from less than 9% to over 44%. In real terms, from the approximately eight million women of 50 years old and over in Spain, the number eligible for treatment would range from 0.7 to 3.8 million, depending on the guideline used. A huge proportion of inappropriate treatments was found when applying these guidelines to the Spanish population, combining a high overuse (42–78% depending on the guideline used) and underuse (7–41%). In conclusion, we found that the pharmacological management of osteoporosis in women of 50 and over in this population combines an important overuse and, to a lesser extent, underuse, although the level of inappropriateness varied strikingly depending on the CPG used. It seems urgent to reduce treatment overuse without neglecting underuse, as is urgent an attempt to reach wider agreement worldwide regarding osteoporosis management, in order to facilitate appropriate treatment and development of policies to reduce effectively treatment inappropriateness.

Fulvestrant in postmenopausal women with locally advanced or metastatic breast cancer that has progressed on prior endocrine therapy: a guide

Fulvestrant (Faslodex®) is indicated for the treatment of postmenopausal women with advanced or metastatic breast cancer that has progressed on prior endocrine therapy. A regimen of fulvestrant 500 mg (i.e. 500 mg on days 0, 14 and 28, then 500 mg every 28 days) prolonged the time to disease progression and overall survival to a greater extent than a fulvestrant 250 mg regimen and was generally well tolerated in this patient population.

Effect of minodronate on the speed of sound of the calcaneus in postmenopausal women with an increased risk of fractures: A clinical practice-based observational study

BackgroundWe previously reported that alendronate and risedronate reduce the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) by 44.9% and 34.7%, respectively, at 3 months after the start of treatment, and increase the speed of sound (SOS) of the calcaneus by 0.6% and 0.65%, respectively, at 12 months after the start of treatment in postmenopausal women with osteoporosis. The aim of the present clinical practice-based observational study was to examine the effect of treatment with minodronate for 12 months on the SOS of the calcaneus and on bone turnover markers in postmenopausal women with an increased risk of fractures. MethodsForty-two postmenopausal women with osteoporosis or osteopenia with a clinical risk factor for fractures who had been treated with minodronate for > 12 months were enrolled in the study. The SOS and bone turnover markers were monitored during treatment with minodronate for 12 months. ResultsCompared to their baseline values, the urinary levels of NTX at 3 months and the serum levels of alkaline phosphatase at 12 months were significantly decreased at 47.5% and 25.8%, respectively. At 12 months, the SOS increased modestly, but significantly, by 0.47%, compared to the baseline value. ConclusionThe present study confirmed that minodronate suppressed bone turnover and modestly increased the SOS of the calcaneus in postmenopausal women with an increased risk of fractures.

Neurite outgrowth promoting effect of 17-β estradiol is mediated through estrogen receptor alpha in an olfactory epithelium culture

Olfactory deficits are observed early in the course of chronic neurological disorders including Alzheimer׳s disease (AD). Estrogen treatment in post-menopausal women reduced the incidence of olfactory dysfunction, raising the possibility that estrogen treatment can cure olfactory deficits in preclinical stages of AD. In this study, we examined the estradiol׳s effects on neurite outgrowth in explant cultures of mouse olfactory epithelium (OE). We found that neurons in OE cultures treated with 100pM 17-β estradiol (estradiol) had significantly longer neurite outgrowth than cultures treated with ethanol alone (vehicle). The OE neurons expressed estrogen receptors alpha (ERα) and ER beta (ERβ). Estrogen treatment upregulated both ERα and ERβ expression in OE culture. Treatment of OE cultures with propyl pyrazole triol (PPT), a selective agonist for ERα increased neurite outgrowth to comparable extent as estradiol treatment. In contrast, 2,3-bis-4-hydroxyphenyl (DPN), a specific agonist for ERβ, had no effect on neurite outgrowth. Furthermore, estradiol treatment increased neurite outgrowth in OE cultures derived from ERβ-deficient/knockout mice and wild-type littermates, but not in ERα-deficient/knockout mice. These data suggest that ERα mediates the neurite outgrowth promoting effects of estradiol in OE cultures. We propose that olfactory dysfunction in chronic neurological disorders, where estrogen deficiency is a risk factor, is an indicator of compromised axonal regeneration of olfactory sensory neurons.

Treatment with 17β-estradiol in postmenopausal women is associated with lower PiB-PET retention

Treatments to reduce the amyloid plaque burden in the aging, cognitively normal population may prevent or delay the development of dementia. Pittsburgh compound B (PiB) binds to amyloid plaque and provides a surrogate for amyloid β pathology using PET. PiB-PET retention is a frequent finding in the aging, cognitively normal population. We investigated whether the treatment of postmenopausal women with menopausal hormone therapy (MHT) would have an association with amyloid burden measured by PiB-PET. Participants were recruited from the Kronos Early Estrogen Prevention Study (KEEPS), which was a randomized, placebo controlled trial to evaluate cardiovascular effects of MHT in recently menopausal women. PiB imaging was performed on a subgroup of subjects about 7 years after initiating 4 years of MHT where women within 6-36 months of their last menses had been randomized to either oral conjugated equine estrogen (CEE), Premarin, 0.45mg/day (N=17); or transdermal 17β-estradiol (TE), Climara, 50μg/day (N=21) (each with progesterone 200mg/day for 12 days/month) or placebo pills and patch (N=30). Participants had full clinical and neuropsychometric assessments. PiB images from each group were compared after treatment using a global SUVr measurement as a continuous measure. Positive PiB-PET scans were seen in 3(18%), 1(5%) and 1(3%) with median(range) SUVr's of 1.27 (1.19, 1.76), 1.25 (1.12, 1.75), 1.28 (1.20, 1.44) in the CEE, TE, and placebo groups respectively. A trend for reduced PiB retention was seen in the TE group vs. placebo (p=0.08). Among women who were APOE 4+ (N=18), we observed differences in PiB retention between CEE vs. TE (p=0.049) and TE vs. placebo (p=0.055) groups. No significant differences were observed in APOE 4- participants (n=40). (Figure). Boxplots of PiB ratios by treatment status. For ε4 positive only (right box), the p-values between 3 groups are as follows; CEE vs. Estradiol = 0.049, CEE vs. Placebo = 0.25 and Estradiol vs. Placebo = 0.055. The box on left has all subjects with e4 positives in red. The middle box has e4 negative subjects only. P-values are from Kruskal-Wallis and Wilcoxon rank sum tests. PiB cutoff for positivity at 1.4 is shown by a red-hashed line. These preliminary findings in a small number of women suggest an active role of TE for reducing amyloid brain deposition in postmenopausal women when treated for 4 years, shortly after menopause. These data may provide the rationale for a clinical trial to further investigate these findings in a larger population. These findings would support the observation that 17β-estradiol reduces the release of Aβ peptides in preclinical models. This interaction seems to be most pronounced in APOE 4+ women.

The effect of anastrozole on bone mineral density during the first 5years of adjuvant treatment in postmenopausal women with early breast cancer.

PurposeThe administration of aromatase inhibitors is associated with bone loss in postmenopausal women. We assessed changes in bone mineral density (BMD) from baseline to 60 months of treatment in patients receiving anastrozole as initial adjuvant therapy.MethodsPostmenopausal women with hormone receptor-positive breast cancer receiving anastrozole as adjuvant therapy at our center since 2004 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48 and 60 months. Oral bisphosphonate (Bis) treatment was initiated when patients were diagnosed with osteoporosis having a T-score of −2.5 or lower.ResultsFifty-five patients were enrolled in the study between 2004 and 2011, and the mean follow-up period was 53.6 months. Thirty-five patients were administered Bis (risedronate in 27 patients, alendronate in 8 patients). After 6 months of hormone therapy, BMD decreased by 0.5% from baseline at the lumbar spine (LS) and BMD decreased by 1.5% at the femoral neck (FN). However, BMD increased by 1.9% at the LS and BMD decreased by 1.5% at the FN for 60 months of treatment. In patients treated with upfront Bis (n = 19), 5.4% BMD increase from baseline was noted at the LS whereas in those without Bis (n = 21) BMD decreased by 4.3% from baseline within 24 months (P < 0.0001). Fractures were observed in 4 patients (7.3%), and 1 patient (1.8%) had a fragility fracture.ConclusionsUpfront treatment of Bis with anastrozole significantly increased BMD at the LS and an optimal use of Bis would not increase bone fractures.Trial registrationUMIN0000017571

Low-Dose Intravaginal Estriol and Pelvic Floor Rehabilitation in Post-Menopausal Stress Urinary Incontinence

Introduction: Pelvic floor muscle training (PFMT) and electrical stimulation (ES) are conservative models of therapy for treating female stress urinary incontinence (SUI). The presence of estradiol receptors in the lower urinary tract advances the case for estradiol therapy in SUI. The aim of our study was to investigate the effects of the combination of pelvic floor rehabilitation and intravaginal estriol (IE) on SUI treatment in postmenopausal women. Material and Methods: Sixty-two women with SUI were randomized to PFMT, ES and biofeedback (Group 1) or the same treatment plus 1 mg IE (Group 2) for 6 months. Patients were evaluated with medical history, pelvic examination, urodynamics, 24-hour pad test. Urinary incontinence was evaluated using the International Consultation on Incontinence questionnaire on urinary incontinence short form and quality of life using the Incontinence Impact Questionnaire-Short Form. Results: Two patients were lost at follow-up and one discontinued the study. Mean urine leakage at the 24-hour pad test dropped from 42.3 ± 20.2 g/die to 31.5 ± 14.2 g/die in Group 1 and from 48.3 ± 19.8 g/die to 22.3 ± 10.1 g/die in Group 2. Symptoms scores and incontinence status were statistically significant better in Group 2 when compared to Group 1. Conclusion: IE added to PFMT, ES and BF is a safe and efficacious first-line therapy in postmenopausal women with SUI.

Kyphoplasty versus Conservative Treatment: A Case–Control Study in 110 Postmenopausal Women Population. Is Kyphoplasty Better than Conservative Treatment?

Introduction Osteoporosis is a highly prevalent and one of the most debilitating and costly chronic diseases worldwide and it is also responsible for approximately 1.5 million vertebral fragility fractures (VCFs) a year.1,2,3 Most of the patients experiencing an osteoporotic VCFs remain asymptomatic or minimally symptomatic; however, a large part of these patients do experience significant pain, resulting in decreased quality of life and disability and mortality too.4 The consequences of these fractures include pain and, in many cases, progressive vertebral collapse with resultant spinal kyphosis. Minimally invasive procedures, namely, kyphoplasty and vertebroplasty, represent a recent advance to the treatment of osteoporotic VCFs.5,6,7 The aim of this study is to compare effects in terms of recovery and quality of life and to compare deformity prevention efficacy of kyphoplasty and conservative treatment in postmenopausal women with an osteoporotic VCF. The aim of this study is to provide an efficacy assessment of kyphoplasty as compared with standard conservative treatment in postmenopausal women (bracing immobilization).8,9,10 Patients and Methods We designed a retrospective case–control study on 110 postmenopausal women. Included in this study were patients who were diagnosed with postmenopausal osteoporosis according to National Osteoporosis Foundation (NOF) guidelines, with a recent (&lt; 2 weeks) symptomatic osteoporotic vertebral compression fracture (VCF), no more than two (if any) old VCFs with no resultant kyphotic deformity, and whose treatment starts no later than 15 days from the VCF time. Study population was split in a surgery cohort and a conservative cohort according to the provided treatment. All patients were asked to fill in VAS, SF-12, and Eq. 5D questionnaires at different time points up to 12 months after treatment. Segmental kyphosis at fracture level was also measured for our analysis. Results Kyphoplasty-treated patients had lower back pain VAS scores at 1 month as compared with conservatively treated patients ( p &lt; 0.05). Eq. 5D questionnaire also showed a better quality of life at 1 month for surgically treated patients ( p &lt; 0.05). As for the SF-12 no significant difference was observed. At 12 months, scores from all scales were not statistically different between the two cohorts, although surgically treated patients showed better trends than conservatively treated patients in pain and quality of life. Kyphoplasty was able to restore more than 55% of the original segmental kyphosis, whereas patients in conservative cohort lost 6.67% of the original segmental kyphosis on average. Conclusion Kyphoplasty seems to be a safe and effective procedure in reducing back pain due to painful VCF. The kyphosis restoring effect is also extremely interesting and can be achieved only in the first days after fracture time. In conclusion, kyphoplasty is a procedure that offers a fast recovery and a better quality of life at 1 month after treatment, helping restoring segmental kyphosis after VCFs.11,12,13 Acknowledgments There was no external funding source and no funding source played a role in the investigation. References Who are candidates for prevention and treatment for osteoporosis? Osteoporos Int 1997;7(1):1–6 Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17(12):1726–1733 Iqbal MM, Sobhan T. Osteoporosis: a review. Mo Med 2002;99(1):19–24 Gold DT. The clinical impact of vertebral fractures: quality of life in women with osteoporosis. Bone 1996;18(3, Suppl):185S–189S Jarvik JG, Kallmes DF. Point of view. Efficacy of vertebroplasty and kyphoplasty. Spine 2009;34(6):613–614 Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med 2009;361(6):569–579 Weinstein JN. Balancing science and informed choice in decisions about vertebroplasty. N Engl J Med 2009;361(6):619–621 Lyritis GP, Mayasis B, Tsakalakos N, et al. The natural history of the osteoporotic vertebral fracture. Clin Rheumatol 1989;8(2, Suppl 2):66–69 Prather H, Watson JO, Gilula LA. Nonoperative management of osteoporotic vertebral compression fractures. Injury 2007;38(3, Suppl 3):S40–S48 Garfin SR, Yuan HA, Reiley MA. New technologies in spine: kyphoplasty and vertebroplasty for the treatment of painful osteoporotic compression fractures. Spine 2001;26(14):1511–1515 Ledlie JT, Renfro M. Balloon kyphoplasty: one-year outcomes in vertebral body height restoration, chronic pain, and activity levels. J Neurosurg 2003;98(1, Suppl):36–42 Voggenreiter G. Balloon kyphoplasty is effective in deformity correction of osteoporotic vertebral compression fractures. Spine 2005;30(24):2806–2812 Pradhan BB, Bae HW, Kropf MA, Patel VV, Delamarter RB. Kyphoplasty reduction of osteoporotic vertebral compression fractures: correction of local kyphosis versus overall sagittal alignment. Spine 2006;31(4):435–441

Abstract ES5-1: Adherence and persistence with adjuvant aromatase inhibitor therapy

Abstract Aromatase inhibitors (AI) are medications that inhibit the aromatase enzyme, which converts androgens to estrogens, resulting in suppression of estrogen production in postmenopausal women. Treatment of postmenopausal women diagnosed with hormone receptor positive breast cancer with adjuvant AI therapy for 5 years has resulted in significant improvements in disease free and overall survival. Despite their proven benefit, however, adherence to and persistence with AI therapy is poor. A key reason for non-persistence with therapy is the development of bothersome side effects that can have a negative impact on quality of life. Retrospective analyses have identified possible predictors of poor tolerance of therapy. Studies have also suggested that development of toxicity may be associated with better response to therapy. Because of the concern about non-persistence with therapy, especially in the setting of prescription of an oral medication for many years, there has been considerable research into understanding the mechanism underlying development of toxicity as well as treatment of these side effects. Ultimately the goal is to improve breast cancer survival outcomes while minimizing the negative impact of therapy on quality of life. Citation Format: Norah Lynn Henry. Adherence and persistence with adjuvant aromatase inhibitor therapy [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 ES5-1.

Abstract P6-12-01: A phase I study evaluating AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer

Abstract Background: Preclinical data suggest that patients with ER+ Breast Cancer become less sensitive to hormonal therapy by upregulation of the mTOR pathway. BOLERO-2 demonstrated that the combination of an allosteric mTOR inhibitor and an aromatase inhibitor improves progression-free survival in postmenopausal women with hormone resistant advanced breast cancer (NEJM 2012; 366:520-529). AZD2014 is a selective dual mTORC1 and mTORC2 inhibitor whilst fulvestrant is an estrogen receptor antagonist that is approved for the treatment of postmenopausal women with disease progression following antiestrogen therapy. This phase I trial assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of AZD2014 administered in combination with fulvestrant. Methods: Continuous BID or QD dosing of AZD2014 was administered in combination with fulvestrant 500 mg intramuscularly on day 1 of each 28 day cycle. An additional 500 mg dose of fulvestrant was administered on day 15 of cycle 1 as per the approved dosing schedule. Single and multiple dose AZD2014 and fulvestrant pharmacokinetic samples were obtained. Optional tumor biopsies were also obtained. Results: 43 patients (median age 61, range 32-82 years; prior chemo in the metastatic setting = 25; prior hormonal therapy = 43) have been treated in 4 dosing cohorts: 50 mg BID = 13; 35 mg BID = 6; 100 mg QD = 10; and 75 mg QD = 14. Patients have received 302+ treatment cycles (median 5 cycles/patient, range 1-21) and 4 patients continue on treatment. Review of preliminary unvalidated safety and Pk data revealed that dose-limiting toxicities included rash/mucositis (1 pt) and hyperglycemia (1 pt) at 50 mg BID; fatigue (1 pt) and mucositis (1 pt) at 100 mg QD; and rash (1 pt) at 75 mg QD. Treatment-related toxicities (any grade) include: fatigue (51%), mucositis (60%), rash (60%), nausea (47%), hyperglycemia (12%), and neutropenia (2%). Pharmacokinetic data show that AZD2014 is rapidly absorbed with a median time to maximum concentration of 1-1.75 hours and an estimated mean half-life of approximately 3.3-5.6 hours across the dose range. There is no evidence that co-administration of fulvestrant has a clinically relevant impact on exposure to AZD2014. In the 26 patients with measureable disease, 5 confirmed PRs have been observed (duration 4-18+ months) with an additional 14 patients experiencing stable disease for at least 6 months of treatment. Conclusion: Continuous QD (75mg) and BID (35 and 50 mg) administration of AZD2014 in combination with fulvestrant is tolerable with clinical benefit observed in nearly half of the patients. Toxicities observed are broadly consistent with AEs observed in other trials with antihormonal agents and other mTOR inhibitors, but seem to be well manageable. There were no new or other additive toxicities, when the two drugs were combined and AZD2014 pharmacokinetic data are broadly consistent with what has been previously observed for AZD2014 single agent. A randomized phase II trial of the combination is ongoing and an intermittent weekly dosing schedule is being explored in additional patient cohorts in the current study. Citation Format: Howard Burris III, Patricia LoRusso, W Larry Gluck, Suzanne Jones, Muaiad Kittaneh, Erika Hamilton, Stephen Green, Wendy Burke, Donald Strickland, Elisabeth Oelmann, Manish Patel. A phase I study evaluating AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer [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 P6-12-01.

Economic Evaluations of Everolimus Versus Other Hormonal Therapies in the Treatment of HR+/HER2− Advanced Breast Cancer From a US Payer Perspective

IntroductionThe objective of the study was to assess the cost-effectiveness of EVE+EXE versus endocrine monotherapies in the treatment of postmenopausal women with HR+, HER2− ABC after failure of treatment with nonsteroidal aromatase inhibitors from a US third-party payer perspective. Materials and MethodsA Markov model was developed to evaluate the costs and effectiveness associated with EVE+EXE, exemestane (EXE), fulvestrant (FUL), and tamoxifen (TAM) over a 10-year time horizon. The model included 3 health states: responsive/stable disease, progression, or death. Monthly transition probabilities were estimated based on the BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) data and network meta-analyses. Costs included drug acquisition and administration costs, medical costs associated health states, and costs for managing adverse events (AEs). Utilities for each health state and disutilities for AEs were derived from the literature. Incremental costs per quality-adjusted life year (QALY) were estimated by comparing EVE+EXE with each endocrine monotherapy. One-way and probabilistic sensitivity analyses were performed. ResultsIn the base case, EVE+EXE was associated with 1.99 QALYs and total direct costs of $258,648 over 10 years. The incremental cost per QALY of EVE+EXE was $139,740 compared with EXE, $157,749 compared with FUL, and $115,624 compared with TAM. At a willingness-to-pay threshold of $130,000/QALY or above, EVE+EXE appeared to be the most cost-effective treatment among all drugs. ConclusionsEverolimus with EXE demonstrated QALY improvements compared with 3 other endocrine monotherapies. Benchmarked by the economic value of other novel cancer therapies, EVE+EXE might be considered a cost-effective option compared with endocrine therapies for HR+/HER2− ABC.

Láser erbium vaginal como tratamiento del síndrome genitourinario de la menopausia: resultados preliminares

SUMMARY Background: The genitourinary syndrome of menopause (GSM) affects up to 50% of postmenopausal women. Symptoms are chronic and likely worsen over time. This complains may interfere with sexual function and quality of life. Objective: To evaluate the short-term effectiveness and acceptability of Erbium in yttrium aluminum-garnet crystal Laser (Er:YAG) as a non-invasive, non-ablative photothermal therapy for the treatment of GSM. Methods: Prospective longitudinal study performed in 28 postmenopausal women suffering from GSM. All participants were treated intravaginally with Er:YAG laser in 3 applications performed every 30 days. Symptoms (vaginal dryness and dyspareunia) were evaluated by a visual-analogic scale (VAS) and the vaginal health index score (VHIS). After therapy, the women were asked to evaluate the acceptability of the intervention. Results: Er:YAG laser treatment was effective to improve symptoms (vaginal dryness and dyspareunia; p<0.01) at all the study period, as well the VHIS (8.2 ± 1.3 at baseline vs. 19.2 ± 0.4 after treatment; p<0.01). Satisfaction with the procedure was reported as excellent or good by 93.4% of women. Conclusion: Our pilot study shows that the Er:YAG treatment in postmenopausal women with GSM is effective, feasible, and safe. Further larger, long-term and controlled studies are required to confirm this data.

Clinical benefit of sequential use of endocrine therapies for metastatic breast cancer.

Sequential use of endocrine agents is common in estrogen receptor (ER)-positive metastatic breast cancer (MBC). In premenopausal women with MBC, tamoxifen and/or a luteinizing hormone-releasing hormone (LH-RH) agonist are options for endocrine treatment. Meta-analysis showed that the combination of the two agents is superior to either monotherapy. Under ovarian ablation or function-suppression, an agent used to treat postmenopausal women, such as the aromatase inhibitor (AI), fulvestrant, becomes possible as a subsequent therapy. In postmenopausal women, endocrine treatment options are widely available and an optimal sequence has not yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen, or tamoxifen for patients who have received adjuvant AI. In addition, data suggest that fulvestrant is a promising therapeutic option that has proven efficacy in the treatment of postmenopausal women with MBC. Other agents that may be used in the sequence include a steroidal AI or a progestin. Furthermore, estrogen additive therapy by with diethylstilbestrol or ethinylestradiol has recently been revived and showed a high response rate as a salvage endocrine therapy, although its mechanism of action is still unclear. Thus, sequential use of endocrine therapies, especially the use of a subsequent therapy with a different mechanism of action to the prior therapy, has a beneficial effect in maintaining a good quality of life and extending survival for MBC with hormone responsiveness.

A systematic review of non-hormonal treatments of vasomotor symptoms in climacteric and cancer patients.

The cardinal climacteric symptoms of hot flushes and night sweats affect 24-93% of all women during the physiological transition from reproductive to post-reproductive life. Though efficacious, hormonal therapy and partial oestrogenic compounds are linked to a significant increase in breast cancer. Non-hormonal treatments are thus greatly appreciated.This systematic review of published hormonal and non-hormonal treatments for climacteric, and breast and prostate cancer-associated hot flushes, examines clinical efficacy and therapy-related cancer risk modulation.A PubMed search included literature up to June 19, 2014 without limits for initial dates or language, with the search terms, (hot flush* OR hot flash*) AND (clinical trial* OR clinical stud*) AND (randomi* OR observational) NOT review). Retrieved references identified further papers. The focus was on hot flushes; other symptoms (night sweats, irritability, etc.) were not specifically screened. Included were some 610 clinical studies where a measured effect of the intervention, intensity and severity were documented, and where patients received treatment of pharmaceutical quality. Only 147 of these references described studies with alternative non-hormonal treatments in post-menopausal women and in breast and prostate cancer survivors; these results are presented in Additional file 1.The most effective hot flush treatment is oestrogenic hormones, or a combination of oestrogen and progestins, though benefits are partially outweighed by a significantly increased risk for breast cancer development.This review illustrates that certain non-hormonal treatments, including selective serotonin reuptake inhibitors, gabapentin/pregabalin, and Cimicifuga racemosa extracts, show a positive risk-benefit ratio.Key pointsSeveral non-hormonal alternatives to hormonal therapy have been established and registered for the treatment of vasomotor climacteric symptoms in peri- and post-menopausal women.There are indications that non-hormonal treatments are useful alternatives in patients with a history of breast and prostate cancer. However, confirmation by larger clinical trials is required.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-0808-y) contains supplementary material, which is available to authorized users.

Update on denosumab treatment in postmenopausal women with osteoporosis.

Denosumab, a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), blocks binding of RANKL to the RANK receptor, found on the surface of osteoclasts and osteoclast precursors, resulting in decreased bone resorption. Subcutaneous denosumab administration once every 6 months increases bone mineral density at the lumbar spine, total hip, and/or femoral neck, and reduces markers of bone turnover significantly in postmenopausal women with osteoporosis. Relative to placebo, denosumab treatment reduces the risk of vertebral, nonvertebral, and hip fractures significantly. The benefits of denosumab treatment are generally obvious after the first dose and were continued for up to 8 years of treatment in an extension study. The tolerability profile of denosumab during this extension phase was consistent with that observed during the initial 3-year FREEDOM trial. Postmarketing safety surveillance has not shown any unexpected findings. Ongoing safety surveillance will more fully define the long-term safety of denosumab. The benefits of denosumab would seem to be greater than its risks. Denosumab is an important choice in the treatment of postmenopausal women with osteoporosis at increased risk of fractures, including older patients who have difficulty with oral bisphosphonate intake and patients who are intolerant of, or unresponsive to, other therapies.