High-risk Postmenopausal Women Research Articles

Sclerostin as a Genetic Determinant of Trabecular Bone Score in Postmenopausal Women: The Bushehr Elderly Health (BEH) Program.

Sclerostin, a protein encoded by the SOST gene, is an important genetic risk factor for osteoporosis in postmenopausal women. This study was conducted on the Iranian postmenopausal women, to investigate the association between this gene and the Trabecular Bone Score (TBS) as a novel index used for assessing osteoporosis. The present study, conducted in 2024, was performed on 1071 women aged 60 years and older who participated in the Bushehr Elderly Health (BEH) program. The associations between seven independent Single Nucleotide Polymorphisms (SNPs) within the SOST gene and mean TBS of L1 to L4 were examined using the additive, dominant, and recessive models. Genetic risk scores (GRS) were calculated for each postmenopausal woman based on the coefficient regressions derived from the additive and dominant models. The relationship between the GRS quartiles and TBS was evaluated using a linear regression model. After adjusting for age and Body Mass Index (BMI), the associations between the rs2023794-C and TBS were significant in the additive (β = 0.03, P= 4.7×10-5, PFDR= 0.0003) and dominant (β = 0.032, P= 5×10-5, PFDR= 0.0003) models. The GRS derived from both additive and dominant models were related to TBS (P<0.05). For the additive model GRS, TBS showed an average increase of 0.022 score for the fourth quartile in comparison with the first quartile, adjusted for age, BMI, type 2 diabetes mellitus (T2DM), and smoking status (P=0.001). SOST gene is associated with TBS and may have implications for personalized medicine. Targeting sclerostin through SOST could offer a therapeutic approach in managing osteoporosis in high-risk postmenopausal women.

Abstract 782: Correlation between collagen peptides and physical features of fibrosis in breast tissue from women at increased risk of cancer

Abstract Breast cancer risk increases significantly in women who maintain higher radiologically dense breast tissue as they age. However, the mechanisms that underlie this association remain poorly understood, especially in postmenopausal women. A predominant contributor to dense breasts and differences between women is the relative amount of fibrillar collagens. Experimental models suggest that changes in collagen properties such as fiber alignment and stiffness promote local stromal fibrosis, which we hypothesize may contribute to the relationship between breast density, aging, and tumorigenesis. Normal breast biopsy samples from the contralateral, healthy breast of 32 postmenopausal breast cancer patients participating in a clinical trial for drug effect on breast density were examined and scored for areas of fibrosis and analyzed using second harmonic generation microscopy (SHG) and mass spectrometry proteomics. Our aim was to identify areas of fibrosis and relate the severity of focal fibrosis to the physical properties and peptide composition of collagen fibers. Using GraphPad Prism, we conducted one-way ANOVA and Kruskal-Wallis tests and post-hoc multiple comparison tests. H&amp;E-stained breast tissue samples were scored according to percent fibrosis. The minimum and maximum percent fibrosis were 5% and 100%, respectively, with a median of 60% (95% CI: 97.06%). Out of 31 people, 16 had a higher fibrosis score than the median. Consistent with pathologic scoring of the presence and extent of fibrosis, fiber counts were significantly lower in tissue with lower fibrosis scores than samples with more highly scored fibrosis (p-value &amp;lt;0.001). Distance to the nearest fiber was greater in samples with &amp;lt; 20% fibrosis, whereas greater alignment to the nearest fiber was observed in higher fibrosis percentages. At the molecular level, 22 peptides demonstrated a strong correlation with percent fibrosis (spearman r ≥ 60), of which 13 peptides were statistically significant (p-value &amp;lt;0.0001). The putatively identified peptides belong to type I, III, IV and VI collagens. Fiber length and straightness, but not fiber width, were higher in tissues with greater percent fibrosis. Significant correlations were identified between collagen physical features and peptides: two distinct peptides correlated with collagen fiber length and straightness while 20 peptides correlated with fiber width. These putative peptides belong to types I, III, IV and V collagens with ~70% of the peptides containing at least one hydroxyproline modification. This study is the first to explore the link between focal fibrosis and collagen-associated peptides in healthy breast tissue of high-risk postmenopausal women. These findings provide novel insights on stromal collagens associated with fibrotic changes in normal at-risk breast tissue that may act in tissue susceptibility to tumor formation. Citation Format: Denys Rujchanarong, Alison T. Stopeck, Christina Preece, Ren Sun, Pavani Chalasani, Sean Brown, Ji D. Bai, Heather Jensen Smith, Sungyong You, Peggi M. Angel, Patricia Thompson. Correlation between collagen peptides and physical features of fibrosis in breast tissue from women at increased risk of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 782.

Anastrozole for the prevention of breast cancer in high-risk postmenopausal women: cost-effectiveness analysis in the UK and the USA

PurposeThe effectiveness of anastrozole for breast cancer prevention has been demonstrated. The objective of this study was to evaluate the cost-effectiveness of anastrozole for the prevention of breast cancer in women with a high risk of breast cancer and to determine whether anastrozole for the primary prevention of breast cancer can improve the quality of life of women and save health-care resources.MethodsA decision-analytic model was used to assess the costs and effects of anastrozole prevention versus no prevention among women with a high risk of breast cancer. The key parameters of probability were derived from the IBIS-II trial, and the cost and health outcome data were derived from published literature. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for the two strategies,One-way and probabilistic sensitivity analyses were performed.ResultsIn the base case, the incremental cost per QALY of anastrozole prevention was £125,705.38/QALY in the first 5 years compared with no prevention in the UK, above the threshold of WTP (£3,000/QALY),and in the 12-year period, the ICER was £8,313.45/QALY, less than WTP. For the US third-party payer, ICER was $134,232.13/QALY in the first 5 years and $8,843.30/QALY in the 12 years, both less than the WTP threshold ($150,000/QALY).ConclusionIn the UK and US, anastrozole may be a cost-effective strategy for the prevention of breast cancer in high-risk postmenopausal women. Moreover, the longer the cycle of the model, the higher the acceptability. The results of this study may provide a scientific reference for decision-making for clinicians, patients, and national medical and health care government departments.

Molecular Subtype Classification of Postmenopausal Osteoporosis and Immune Infiltration Microenvironment Based on Bioinformatics Analysis of Osteoclast-Regulatory Genes.

Osteoporosis is common in postmenopausal women but is often asymptomatic until a fracture occurs, highlighting the importance of early screening and preventive interventions. This study aimed to develop molecular subtype risk stratification of postmenopausal osteoporosis and analyze the immune infiltration microenvironment. Microarray data for osteoporosis were downloaded and analyzed. Logistic and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct the molecular risk model. Circulating blood samples were collected from 10 enrolled participants to validate the key differentially expressed genes, and consistent clustering based on the expression profiles of candidate genes was performed to obtain molecular subtypes. Three key genes, CTNNB1, MITF, and TNFSF11, were obtained as variables and used to construct the risk model. External experimental validation showed substantial differences in the three key genes between patients with osteoporosis and the controls (p < 0.05). Three subtypes were obtained based on dimensionality reduction clustering results. Cluster 3 had significantly more patients with low bone mineral density (BMD), whereas Cluster 2 had significantly more patients with high BMD (p < 0.05). This study introduced a novel molecular risk model and subtype classification system, which is an evidence-based screening strategy that will guide the active prevention, early diagnosis, and treatment of osteoporosis in high-risk postmenopausal women.

Breast cancer prevention with liquiritigenin from licorice through the inhibition of aromatase and protein biosynthesis in high-risk women’s breast tissue

Breast cancer risk continues to increase post menopause. Anti-estrogen therapies are available to prevent postmenopausal breast cancer in high-risk women. However, their adverse effects have reduced acceptability and overall success in cancer prevention. Natural products such as hops (Humulus lupulus) and three pharmacopeial licorice (Glycyrrhiza) species have demonstrated estrogenic and chemopreventive properties, but little is known regarding their effects on aromatase expression and activity as well as pro-proliferation pathways in human breast tissue. We show that Gycyrrhiza inflata (GI) has the highest aromatase inhibition potency among these plant extracts. Moreover, phytoestrogens such as liquiritigenin which is common in all licorice species have potent aromatase inhibitory activity, which is further supported by computational docking of their structures in the binding pocket of aromatase. In addition, GI extract and liquiritigenin suppress aromatase expression in the breast tissue of high-risk postmenopausal women. Although liquiritigenin has estrogenic effects in vitro, with preferential activity through estrogen receptor (ER)-β, it reduces estradiol-induced uterine growth in vivo. It downregulates RNA translation, protein biosynthesis, and metabolism in high-risk women’s breast tissue. Finally, it reduces the rate of MCF-7 cell proliferation, with repeated dosing. Collectively, these data suggest that liquiritigenin has breast cancer prevention potential for high-risk postmenopausal women.

Osteoporosis: Recent Advances

Osteoporosis is characterized by low bone mass, microarchitectural disruption, and skeletal fragility, resulting in decreased bone strength and an increased risk of fracture. Decreased bone strength is related to many factors in addition to bone mineral density (BMD), including rates of bone turnover, bone geometry, and microarchitecture.Osteoporosis has no clinical manifestations until there is a fracture. Complications of fractures include pain, deformity, disability, and loss of height. A clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis, without measurement of BMD.In the absence of a fragility fracture, BMD assessment by dual-energy x-ray absorptiometry (DXA) is the standard test to diagnose osteoporosis, according to the classification of the World Health Organization. A DXA T-score d”-2.5 is consistent with osteoporosis, whereas a T-score between -1 and -2.5 isosteopenia.All postmenopausal women with osteoporosis should have a history, physical examination, and basic laboratory evaluation. Initial laboratory studies should include a complete blood count (CBC), biochemistry profile, and 25- hydroxyvitamin D (25[OH]D).The need for additional laboratory evaluation depends upon the initial evaluation and Z-score. Women who have abnormalities on initial laboratory testing, suspicious findings on history and physical examination suggesting a secondary cause of osteoporosis, or Zscores d”-2 may require additional evaluation for these secondary causes.Lifestyle measures should be adopted universally to reduce bone loss in postmenopausal women. Lifestyle measures include adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol use. In general, 1200 mg of elemental calcium daily, total diet plus supplement, and 800 international units of vitamin D daily are advised. Many patients require vitamin D supplementation as it is difficult to achieve goals with diet alone. Postmenopausal women with established osteoporosis (T-score d”-2.5) or fragility fracture be treated with a pharmacologic agent. For the treatment of high-risk postmenopausal women with T-scores between -1.0 and -2.5, better to start pharmacologic therapy. Most women, for the initial treatmentoral bisphosphonates is good choice.For severe osteoporosis, some experts prefer initial treatment with an anabolic agent, whereas other experts prefer initial treatment with bisphosphonates. Teriparatide and abaloparatide are good anabolic agent. Romosozumab is an alternative. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 194

Optimal breast cancer risk reduction policies tailored to personal risk level.

Depending on personal and hereditary factors, each woman has a different risk of developing breast cancer, one of the leading causes of death for women. For women with a high-risk of breast cancer, their risk can be reduced by two main therapeutic approaches: 1) preventive treatments such as hormonal therapies (i.e., tamoxifen, raloxifene, exemestane); or 2) a risk reduction surgery (i.e., mastectomy). Existing national clinical guidelines either fail to incorporate or have limited use of the personal risk of developing breast cancer in their proposed risk reduction strategies. As a result, they do not provide enough resolution on the benefit-risk trade-off of an intervention policy as personal risk changes. In addressing this problem, we develop a discrete-time, finite-horizon Markov decision process (MDP) model with the objective of maximizing the patient's total expected quality-adjusted life years. We find several useful insights some of which contradict the existing national breast cancer risk reduction recommendations. For example, we find that mastectomy is the optimal choice for the border-line high-risk women who are between ages 22 and 38. Additionally, in contrast to the National Comprehensive Cancer Network recommendations, we find that exemestane is a plausible, in fact, the best, option for high-risk postmenopausal women.

A randomized presurgical trial of alternative dosing of exemestane in postmenopausal women with early-stage ER-positive breast cancer.

519 Background: Successful therapeutic cancer prevention requires definition of the minimal effective dose of the proposed agent. Aromatase inhibitors substantially decreased breast cancer incidence in high risk postmenopausal women in phase III trials but their clinical use in prevention and adherence in adjuvant setting is limited by adverse events. We conducted a randomized presurgical phase IIb trial to evaluate two alternative doses of exemestane. Methods: We conducted a multi-center, pre-surgical, double-blind, 3-arm, non-inferiority phase IIb study in postmenopausal women with histologically confirmed estrogen receptor (ER)-positive breast cancer. Patients were randomized to receive either exemestane 25 mg/day (QD), or 25 mg/three times/week (TIW), or 25 mg once a week (QW) for 4-6 weeks before surgery. Blood and tissue biomarkers were collected at baseline and final visit. The primary aim was a non-inferiority percent change of circulating estradiol relative to the standard dose. Secondary endpoints were the change in Ki-67 and PgR expression in cancer tissue, blood sex hormones, lipid profile, toxicity and menopausal symptoms. For the power calculation we assumed a non-inferiority difference of 6% in the percentage change of estradiol among arms, using a one-sided, two-sample t-test. Assuming a 10% drop-out rate, a total sample size of 180 participants (60 per arm) had 80% power to detect a 6% margin of equivalence. The significance level for the main endpoint was 0.025 to account for multiple comparisons and 0.05 for secondary endpoints. Results: A total of 230 women were screened, 180 agreed to participate and 173 were evaluable for response. The median percent change of estradiol was -98%, -98%, and -70% for exemestane QD (n = 56), TIW (n = 57), and QW (n = 60), respectively, showing no significant difference between QD and TIW arms (p = 0.9). Similarly, no differences were observed for estrone, total estrone and estrone sulfate between QD and TIW arms. The QW arm showed some modulation in all hormones, even though less significantly so. Among the secondary endpoints, Ki-67 and PgR were reduced in all arms, with a median change of -5% vs -7.5% for Ki-67(p = 0.124), and -9 vs -17 for PgR (p = 0.246) in the TIW vs QD arms, respectively. SHBG and HDL-cholesterol had a more favorable profile with the TIW dose compared to the daily dose. Adverse events, measured according to the CTCAE (v4), and menopausal symptoms according to MENQOL were similar in all arms, but the short treatment time may not be representative. Conclusions: Exemestane 25 mg TIW retains a comparable activity than 25 mg QD. This activity was similar in both arms throughout the primary and the main secondary endpoints. This new schedule should be further assessed in prevention studies and in women on adjuvant treatment who do not tolerate the daily dose. Clinical trial information: NCT02598557.

Abstract P1-11-01: Modulation of the high risk postmenopausal breast tissue genomic profiles with licorice and its bioactive compounds

Abstract Introduction: Breast cancer risk continues to rise following menopause, despite the cessation of ovarian estrogen synthesis. High risk women are often hesitant to take anti-endocrine therapies for breast cancer prevention. Therefore, alternative strategies with greater acceptability are needed. Popular botanicals for menopausal health such as licorice (Glycyrrhiza inflata, GI) and its bioactive compounds liquiritigenin (LigF, phytoestrogen) and licochalcone A (LicA, chalcone) have been studied for their targeted estrogenic and chemopreventive properties in vitro and in vivo. However, their effects on the breast tissue of high risk women are understudied. We hypothesize that these agents create a tumor preventive environment in the breast by locally modulating metabolism, steroid hormone biosynthesis, inflammation, antioxidant response, and proliferation. Methods: We prepared organoids from fresh surgically removed contralateral unaffected breast tissue of 6 high-risk postmenopausal women undergoing bilateral mastectomy due to incident unilateral breast cancer. We exposed these organoids to DMSO (control), GI (5 µg/mL), LigF (5 µM), and LicA (5 µM) for 24 h. After total RNA sequencing, we performed differential gene expression between treatments and controls using the limma R package. Enrichment results were generated by analyzing the up-regulated and down-regulated gene sets using Enrichr. A gene ontology (GO) pathway analysis was performed. The enriched pathways with combined enrichment scores &amp;gt; 4 and FDR &amp;lt; 0.05 were considered statistically significant. Results: Among the top ranked biological pathways we observed significant upregulation of Nrf2 and phase II metabolism pathways, and the downregulation of steroid biosynthesis, metabolic processes such as estrogen metabolism, citrate cycle, serine and one carbon metabolism, as well as the cell cycle and DNA replication in GI treated samples. For LigF treated group, significant downregulation of inflammatory response, cell cycle, and the integrated breast cancer pathways were among the top ranked processes. For LicA treated samples, pathways associated with glutathione metabolism, Nrf2, response to oxidative stress, and unfolded protein response were significantly upregulated while steroid hormone biosynthesis, lipid metabolism, fatty acid biosynthesis, and glucose metabolism were among the top ranked downregulated pathways.Conclusions: Our data suggests that GI and its components LigF and LicA can modulate breast microenvironment by reducing inflammation, steroid hormone biosynthesis, cellular metabolism, and proliferation. They can also enhance protection against oxidative and cellular stress. These observations along with the popularity of natural products, suggests that licorice GI and its bioactive compounds might have the potential to create a tumor preventive breast microenvironment in high risk postmenopausal women, and need to be further studied. Citation Format: Atieh Hajirahimkhan, Shao-Nong Chen, Guido F Pauli, Elizabeth Bartom, Susan Clare, Seema A Khan. Modulation of the high risk postmenopausal breast tissue genomic profiles with licorice and its bioactive compounds [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-11-01.

Abstract 2566: The potential role of licorice and its bioactive compounds in promoting a tumor preventive environment in the postmenopausal breast

Abstract Introduction: our purpose was to define if licorice and its main bioactive compounds can suppress aromatase expression/activity and Nrf2 dependent detoxification pathways in the postmenopausal breast. This chemopreventive potential has not previously been reported in preclinical models of high-risk postmenopausal breast. Methods: Inhibition of aromatase activity by three licorice extracts (Glycyrrhiza species), and their bioactive compounds, (liquiritigenin; LigF, isoliquiritigenin; LigC, 8-prenylapigenin; 8-PA, and licochalcone A; LicA) were evaluated fluorometrically, using aromatase supersomes. Computational docking was performed to assess the binding of the bioactive compounds to the binding pocket of aromatase crystal structure compared to the known aromatase inhibitors, letrozole (non-steroidal) and exemestane (steroidal). Using qPCR, the effects of treatments on the expression of aromatase (CYP19A1) mRNA and Nrf2 dependent detoxification enzyme NADPH:quinone oxidoreductase 1 (NQO1) in breast microstructures obtained from high risk postmenopausal women were evaluated. Results: Among the three medicinally used licorice species, Glycyrrhiza inflata (GI) showed the highest aromatase inhibitory potency (IC50 ≈ 1 µg/mL). Licorice phytoestrogens, LigF (400 nM or 0.1 µg/mL), and 8-PA (IC50 ≈ 590 nM or 0.2 µg/mL) exhibited the highest potency compared to the other tested licorice compounds. Computational docking suggested that these phytoestrogens bind to the aromatase binding pocket like the aromatase inhibitor, letrozole. This effect was not observed with non-estrogenic bioactive compounds of licorice, LigC and LicA (specific to GI). In breast microstructures obtained from high risk postmenopausal women, expression of aromatase mRNA was suppressed by GI (30%, P &amp;lt; 0.05), LigF (20%, P &amp;lt; 0.05), and LicA (45%, P &amp;lt; 0.05), while the expression of NQO1 mRNA was enhanced by LicA (200%, P &amp;lt; 0.0001). Conclusions: Licorice species, and their bioactive compounds inhibited aromatase activity in vitro. In the breast microstructures, GI, its compounds LigF and LicA suppressed aromatase expression, and LicA enhanced NQO1 induction, significantly. Further studies will further elucidate the potential of these natural products for promoting a breast tumor preventive environment in postmenopausal women. Citation Format: Atieh Hajirahimkhan, Caitlin Howell, Shao-Nong Chen, Susan E. Clare, Guido F. Pauli, Judy L. Bolton, Birgit M. Dietz, Seema A. Khan. The potential role of licorice and its bioactive compounds in promoting a tumor preventive environment in the postmenopausal breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2566.

Abstract OT-02-01: A longitudinal study assessing sexual dysfunction in postmenopausal women with breast cancer undergoing adjuvant treatment

Abstract According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), Female Sexual Dysfunction is defined as a sexual problem associated with personal distress. It can be caused by any of the following: lack of sexual desire, impaired arousal, inability to achieve orgasm, or pain with sexual activity. Several studies have demonstrated the negative impact chemotherapy has on sexual functioning, short term and long term in women undergoing breast cancer treatment. Most of the research that has been done in this area only evaluated this problem in premenopausal women. The limited studies investigating this in postmenopausal women have found similar effects in this population group. The goal of this study is to assess sexual dysfunction in high risk postmenopausal women with breast cancer undergoing adjuvant therapy. We want to define this problem in this poorly studied subgroup, and to assess the degree of dysfunction, time course over which it occurs, and the particular sexual domains this occurs in. T This longitudinal study will assess sexual functioning utilizing two survey tools- the Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale (FSDS-R). The FSFI is a 19- item questionnaire that assesses six domains of sexual functioning: desire, arousal, lubrication, orgasm, satisfaction, and pain The FSFI has been proven to have excellent validity and reliability in determining sexual dysfunction in healthy women, as well as women with various cancers including breast cancer. It was designed to be easy to use, and can be used in heterosexual, as well as homosexual women. To be consistent with the DSM 5’s definition of sexual dysfunction regarding personal distress, which is not evaluated in the FSFI, the FSDS-R will be utilized. This is a 13-item questionnaire, which has demonstrated excellent validity and reliability in determining sexual distress associated with sexual dysfunction. Participants will serve as their own control while assessing any change in sexual functioning over the course of the administration of 2-3 survey sets. The 1st set of surveys will be administered prior to receiving any treatments, this will serve as a baseline assessment for future comparison. The last 1-2 survey sets will be administered 6 months to 1 year after the initiation of adjuvant therapy. Data will be analyzed with a Repeated Measures ANOVA if statistical assumptions are met. If statistical assumptions are not met the Friedman ANOVA will be used. Post-Hoc testing will be conducted if significant main effects are found. At this time, 13 patients are currently enrolled in this trial. The number of participants for this study to achieve statistical power was calculated to be n=42. This calculation was based on one treatment group, with three observations across time, a correlation amount of repeated measures of 0.5, and a non-sphericity correction of 1.0. The assumed effect size was small to moderate with an F=0.20, an alpha of 0.05, and a beta of 0.20. Eligibility Criteria for this trial: •Must be a postmenopausal female •Diagnosed with Stage I, II, or III breast cancer •Not currently receiving endocrine therapy or chemotherapy•Plans with their physician to receive adjuvant therapy For more information please contact: Heidi Worth, MD PGY2 Internal Medicine Resident University of Tennessee Medical Center, Knoxville 904-540-1286 hworth@utmck.edu Citation Format: Heidi Worth, Timothy Panella, Clayton Bell, Mark Rasnake, Patricia Roberson, Lauren Lewis. A longitudinal study assessing sexual dysfunction in postmenopausal women with breast cancer undergoing adjuvant treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-02-01.

Cost-effectiveness of denosumab for high-risk postmenopausal women with osteoporosis in Thailand

Aims: This study assessed the cost-effectiveness of denosumab for treating postmenopausal women with osteoporosis (PMO) at high risk of fracture in Thailand.Materials and methods: A published Markov cohort cost-effectiveness model was populated with country-specific data as available and other published data as needed. The model used a societal perspective, lifetime horizon, efficacy data from network meta-analysis of trials, and included costs for direct medical and non-medical care, informal care, and osteoporosis treatments to compare denosumab to no pharmacologic treatment (calcium and vitamin D supplements only) and to oral weekly alendronate. The base case (high-risk population) included postmenopausal women with femoral neck T-score ≤−2.5, mean age 65 years at entry, and history of vertebral fracture.Results: High-risk women with osteoporosis using denosumab had the greatest number of life years and quality-adjusted life-years (QALYs) with higher reductions in hip and vertebral fracture incidence compared with patients with no pharmacologic treatment. The incremental cost-effectiveness ratio (ICER) was 119,575 Thai Baht (THB) per QALY for denosumab versus no pharmacologic treatment and 199,186 THB per QALY for denosumab versus alendronate. Among Thai postmenopausal women with high-risk of fractures, denosumab was cost-effective compared with no pharmacologic treatment at a willingness-to-pay threshold of 160,000 THB per QALY. One-way sensitivity analysis showed models were most sensitive to changes in denosumab pricing.Limitations: Data from other countries used when country-specific data were unavailable may not accurately reflect the true experience in Thailand. The model focused explicitly on hip, vertebral, and wrist fractures, and therefore provides a conservative estimate of the overall potential impact of osteoporosis-related fracture. The fracture risk was not adjusted to reflect potential changes in risk after denosumab treatment discontinuation.Conclusions: In Thailand, denosumab offers a cost-effective osteoporosis treatment option versus no pharmacologic treatment in postmenopausal women at high risk of fracture.

Abstract OT1-04-03: Alternative dosing of exemestane before surgery in postmenopausal patients with stage 0-II estrogen receptor positive breast cancer: Design and methodology

Abstract Background: The aromatase inhibitor exemestane (EXE) has shown to lower cancer incidence in high-risk postmenopausal women. However, undesirable symptoms and side effects (i.e., bone density loss, musculoskeletal ache, climacteric syndrome) may compromise patient motivation and adherence to a long-term preventive treatment. A less frequent drug schedule, compared to the standard regimen, may be more acceptable to healthy at-risk women. We hypothesized that comparison of two alternative less frequent dose regimens with the standard daily dose regimen will show that it is possible to decrease undesirable symptoms of EXE while still effectively reducing serum estradiol. Trial Design: We are conducting a multi-center, pre-surgical, double-blind, non-inferiority phase IIb study in which 180 postmenopausal women will be randomized to receive either EXE 25 mg/day or 25 mg/three times a week or 25 mg/week for 4 to 6 weeks prior to surgery. Surgery will occur on day 29, 36 or 43 after treatment initiation. Eligible subjects are postmenopausal women with histologically-confirmed ER-positive (ER &amp;gt;10%) primary breast cancer candidates for surgery. Participants with T0-2, N0-1, Mx or with larger tumors who refuse neo-adjuvant therapy before surgery are eligible. Subjects are stratified according to participating site and body mass index (&amp;lt;25 kg/m2 versus &amp;gt;25 kg/m2). The primary objective is to assess if the reduction in estradiol with EXE 25 mg/three times a week and EXE 25 mg/week is comparable with the standard dose of 25 mg/day of EXE. Methods: Blood will be collected at baseline and at the end of treatment. Tissue samples will be collected from the diagnostic biopsy and at the time of surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery in the three arms in a CLIA certified laboratory. Given the expected reduction of at least 80% change with EXE at 25 mg daily considered as reference group (control arm) against 25 mg/three times a week or 25 mg weekly, for the power calculation we assume a non-inferiority difference of 6% in percentage changes of circulating estradiol after treatment from baseline, using a one-sided, two-sample t-test. Secondary outcome measures are the incidence of toxicity and menopausal symptoms according to the CTCAE (v4) and by the self-administered MENQoL; the effect of the three regimens on sex hormones (estrone, estrone sulphate, SHBG, testosterone, DHEAS and FSH) and the effect on circulating estradiol levels using an ultrasensitive method given that the serum levels in postmenopausal women under EXE may be very low. Drug and metabolites levels will be measured in blood, cancer tissue and non-cancer tissue. Evaluation of serum insulin, glucose (homeostatic model assessment index), and lipid profile (total cholesterol, high-density lipoprotein cholesterol and triglycerides), leptin and adiponectin will be performed before and after treatment. Additionally, we will measure breast estradiol concentration in cancer and non-cancer tissue and compare changes in ER, PgR, and proliferation in cancer and non-cancer tissue samples obtained at time of biopsy and definitive surgery. Finally, we will also analyze the role of the polymorphic UGT2B17 gene (involved in EXE and 17-dihydroexemestane metabolism) as well as tissue proteomics. Preliminary results: Enrollment started in February 2017 and as of July 3, 2019, a total of 170/180 participants have been randomized (94% of the expected sample size). Preliminary data will be presented at the conference. IND Sponsor: NCI/DCP NCI contract: HHSN26120120034I Citation Format: Aliana Guerrieri-Gonzaga, Parjhitham Thomas, Andrea DeCensi, Katherine D Crew, Nagi Kumar, Sara Gandini, Lana Vornik, Brandy Heckman-Stoddard, Eva Szabo, Eileen Dimond, Jack Lee, Diane Liu, Matteo Lazzeroni, Sara Cagnacci, Davide Serrano, Mauro D'Amico, Flavio Guasone, Tania Buttiron Webber, Powel Brown, Bernardo Bonanni. Alternative dosing of exemestane before surgery in postmenopausal patients with stage 0-II estrogen receptor positive breast cancer: Design and methodology [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-03.

Romosozumab or alendronate for fracture prevention in East Asian patients: a subanalysis of the phase III, randomized ARCH study

SummaryRomosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. Among high-risk postmenopausal East Asian women, romosozumab followed by alendronate was associated with lower incidences of fractures vs alendronate alone. Romosozumab demonstrates potential to address an unmet need in osteoporosis management in Asia.IntroductionRomosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. The global ARCH study demonstrated superiority of romosozumab followed by alendronate in reducing fracture risk in high-risk postmenopausal osteoporotic women vs alendronate alone. We report outcomes among ARCH East Asian patients.MethodsIn ARCH, 4093 postmenopausal osteoporotic women with fragility fracture were randomized 1:1 to monthly romosozumab 210 mg or weekly alendronate 70 mg for 12 months, both followed by open-label alendronate. Primary endpoints were incidence of new vertebral fracture (VF) at 24 months and clinical fracture at primary analysis (confirmed fractures in ≥ 330 patients and all patients had opportunity to attend month 24 visit). This post hoc analysis was not powered to detect fracture-rate differences.ResultsThis analysis included 275 patients from Hong Kong, Korea, and Taiwan. Romosozumab followed by alendronate reduced risk of new VFs at 24 months by 60% (P = 0.11) and clinical fractures at primary analysis by 44% (P = 0.15) vs alendronate alone. Romosozumab followed by alendronate significantly increased mean bone mineral density at 24 months from baseline by a further 9.0%, 3.3%, and 3.0% at the lumbar spine, total hip, and femoral neck vs alendronate alone. Adverse event (AE) rates, including positively adjudicated serious cardiovascular AEs (1.6% vs 1.4% at 12 months for romosozumab vs alendronate), were similar across treatment groups.ConclusionsConsistent with the global analysis, romosozumab followed by alendronate was associated with lower incidences of new vertebral, clinical, non-vertebral, and hip fractures vs alendronate alone among East Asian patients.

Bazedoxifene for the treatment of osteoporosis

ABSTRACTIntroduction: Bazedoxifene (BZD) is a third-generation selective estrogen receptor modulator approved for the treatment of postmenopausal osteoporosis with additional favorable effects in lipids, uterine and breast tissue.Areas covered: In this review, the authors outline clinical data regarding the efficacy, safety, and tolerability of continuous BZD administration up to seven years in randomized, placebo-controlled, phase III clinical trials. Long-term treatment with BZD for postmenopausal osteoporosis is generally safe and well tolerated. BZD achieves small but significant increases in the bone mineral density of the lumbar spine but not the total hip. In addition, BZD reduces significantly the risk of vertebral fractures but not of non-vertebral and hip fractures, with the exception of high fracture risk postmenopausal women in whom BZD significantly reduces non-vertebral fractures.Expert opinion: BZD does not seem to offer significant advantages over the other available antiresorptive agents. However, considering the need for long-term management of osteoporosis, BZD may have a place in the long-term therapeutic planning of the disease.

Abstract 4216: Adiponectin, leptin and breast cancer in high risk postmenopausal women: Results from a nested case-control study

Abstract Introduction: Obesity is a risk factor for postmenopausal breast cancer (BC) and evidence supports the pivotal role of adipokines in the association between obesity and BC. In the present study, we aim to investigate the role of adiponectin and leptin as independent risk markers for postmenopausal BC in a prospective nested case-control study within the cohort of women from the International Breast cancer Intervention prevention Study II (IBIS-II). Methods and Results: In the IBIS-II Prevention trial, 3864 healthy postmenopausal women at increased risk for BC were randomized to receive 1 mg/day oral anastrozole or matching placebo for 5 years. We measured serum adiponectin and leptin at baseline and 12-months in 119 cases and 336 controls in the placebo arm, and 57 cases and 165 controls in the anastrozole arm. We performed the adipokines measurements on the automated immunoassay platform ELLA (ProteinSimple, Biotechne). Baseline characteristics (age, body mass index (BMI), smoking status, and oophorectomy) were not different between cases and controls in both trial arms, except for hormone replacement therapy (HRT) use (38.7% of cases vs 51.5% of controls) and hysterectomy (25.2% of cases vs 37.5% of controls) in the placebo arm. We did not observe any statistically significant difference in adiponectin and leptin at baseline between cases and controls in both trial arms. When we considered the change in adiponectin levels between baseline and 12-months of follow-up, we observed a borderline significant higher proportion of BC cases in subjects with a decrease in adiponectin (36.4%) compared to subjects with an increase in adiponectin (25.7%). The multivariate Cox model indicated that women on placebo with a decrease in adiponectin between baseline and 12-months had a 36% significant increased risk in BC (HR=0.64; CI 0.42-0.98; adjusted for age, BMI, previous HRT use, smoking, oophorectomy, hysterectomy). Changes in leptin were not significantly associated with BC incidence overall. However, the multivariate Cox model for the anastrozole arm, indicated a significant higher BC risk for women with the highest increase (&amp;gt;10 ng/ml) vs the lowest decrease (&amp;lt;-10 ng/ml) in leptin: HR=4.45; CI 1.08-18.30; adjusted for age, BMI, previous HRT use, smoking, oophorectomy, hysterectomy. Conclusion: Our results did not support a prognostic role of baseline adiponectin and leptin levels in postmenopausal BC development. However, we observed an increased BC risk in women with a 12-month adiponectin decrease and leptin increase. These data suggest further investigations of changes of adiponectin and leptin levels as attractive targets for BC prevention in postmenopausal women at high risk for BC. Citation Format: Debora Macis, Ivana Sestak, Valentina Aristarco, Harriet Johansson, Aliana Guerrieri-Gonzaga, Andrea Decensi, Bernardo Bonanni, Jack Cuzick, Sara Gandini. Adiponectin, leptin and breast cancer in high risk postmenopausal women: Results from a nested case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4216.

PMS35 - Economic Analysis of Abaloparatide in High-Risk Postmenopausal Women with Osteoporosis in the United States - A Discrete-Event Simulation Model

PMS35 - Economic Analysis of Abaloparatide in High-Risk Postmenopausal Women with Osteoporosis in the United States - A Discrete-Event Simulation Model

Update on Breast Cancer Risk Reduction Therapy

In women at increased risk of breast cancer age ≥35 years, the selective estrogen receptor modulator (SERM) tamoxifen should be discussed as an option to reduce the risk of estrogen receptor (ER)-positive breast cancer. In postmenopausal women, raloxifene, anastrozole, and exemestane should also be discussed as options for breast cancer risk reduction. Risk reduction with SERMs continues for at least 10 years in both premenopausal and postmenopausal women. Tamoxifen is not recommended for women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization. Chemoprevention with a SERM may be particularly beneficial to women with atypical hyperplasia, a 5-year risk of more than 5 %, in women with increased mammographic density, or in women with lobular carcinoma in situ. Aromatase inhibitor therapy is of value in high-risk postmenopausal women. Toxicity with tamoxifen is minimal in premenopausal women and is less with either raloxifene or an aromatase inhibitor in postmenopausal women.

Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia.

Raloxifene is a selective estrogen receptor modulator that has been approved for treating osteoporosis and breast cancer in high-risk postmenopausal women. However, recent evidence suggests that raloxifene adjunct therapy improves cognition and reduces symptom severity in men and women with schizophrenia. In animal models, raloxifene increases forebrain neurogenesis and enhances working memory and synaptic plasticity. It may consequently repair the neuronal and synaptic connectivity that is disrupted in schizophrenia. It also reduces oxidative stress and neuroinflammation, which are potent etiological factors in the neuropathology of schizophrenia. Furthermore, in postmenopausal women, raloxifene reduces the risks for atherosclerosis, diabetes mellitus, and weight gain, which are serious adverse effects associated with long-term antipsychotic treatment in schizophrenia; therefore, it may improve the safety and efficacy of antipsychotic drugs. In this review, recent insights into the neurocognitive, neuroprotective, and cardiometabolic effects of raloxifene in relation to therapeutic outcomes in schizophrenia are discussed.

Abstract ES8-3: Endocrine management of premalignant lesions and DCIS

Abstract It has been recognized for many years that there exist pathological entities associated with an increased risk of invasive breast cancer. The most frequently encountered are atypical hyperplasia (AH), lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS), although other diagnoses have also been identified. Often these lesions are discovered incidentally, and when diagnosed are found to confer a wide range of elevated breast cancer risk. Clinical management of these conditions has largely consisted of surveillance, sometimes with the addition of endocrine therapy. The selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, have been the mainstay of endocrine therapy in this setting. A prospective randomized trial, NSABP P-1 randomized over 13,000 high risk women, defined by a Gail score &amp;gt;1.66, to either 5 years of tamoxifen or placebo.1 Tamoxifen reduced the risk of invasive breast cancer by 49% (p&amp;lt;.00001), with the greatest risk reduction seen in women with ADH or LCIS. The IBIS I study also compared to tamoxifen to placebo and confirmed a risk reduction with tamoxifen, although lower than that reported initially in the P-1 trial (hazard ratio [HR] 0.72 [95% CI 0.59-0.88], p=0.001).2 Most recently, the role of aromatase inhibitors as chemoprevention in this setting has been studied; the results of IBIS II trial, which randomized 3864 high risk postmenopausal women to anastrozole or placebo, found a substantial risk reduction in the AI group (hazard ratio 0.47, 95% CI 0.32-0.68, p&amp;lt;0.0001).3 Endocrine therapy in the adjuvant setting has been reported for DCIS in two prospective clinical studies, the NSABP-B24 and UK/ANZ trials. A meta-analysis of these two trials demonstrated that tamoxifen after lumpectomy for DCIS reduced recurrence of both ipsilateral (HR 0.75; 95% CI 0.61 to 0.92) and contralateral (RR 0.50; 95% CI 0.28 to 0.87) DCIS.4 There was a trend towards decreased ipsilateral invasive cancer (HR 0.79; 95% CI 0.62 to 1.01) and reduced contralateral invasive cancer (RR 0.57; 95% CI 0.39 to 0.83). In addition, the findings of NSABP B-35 randomizing postmenopausal women with ER-positive DCIS reported that 10-year point estimates for DFS were 77.9% for tamoxifen and 82.7% for anastrozole.5 Future challenges for this field will include more precise patient selection for these treatments, as all confer risk of side effects. These have resulted in poor uptake of chemoprevention despite the definitive benefit demonstrated in the large randomized studies. In addition, the utility of endocrine therapy as primary treatment for low risk DCIS or in the neoadjuvant setting are important questions which are currently under investigation. More precise quantification and communication of the risks and benefits of the endocrine therapies will be increasingly needed in order to maximize the benefits of endocrine intervention in this setting. 1Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-88, 1998 2Cuzick J, Sestak I, Cawthorn S, et al: Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 16:67-75, 2015 3Cuzick J, Sestak I, Forbes JF, et al: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383:1041-8, 2014 4Staley H, McCallum I, Bruce J: Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database Syst Rev 10:CD007847, 2012 5Margolese RG: Primary Results of NRG Oncology/NSABP B-35: A Clinical Trial of Anastrozole vs Tamoxifen in Postmenopausal Patients with DCIS. J Clin Oncol 33, 2015 (suppl; abstr LBA500), 2015. Citation Format: Hwang ES. Endocrine management of premalignant lesions and DCIS. [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 ES8-3.