Trial In Postmenopausal Women Research Articles

Efficacy and safety of candidate biosimilar CT-P41 versus reference denosumab: a double-blind, randomized, active-controlled, Phase 3 trial in postmenopausal women with osteoporosis.

To demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis. This 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26weeks, with an equivalence margin of 80-125% (for 95% CIs associated with geometric LS mean ratios). Equivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: - 0.139 [- 0.826, 0.548] in the full analysis set and - 0.280 [- 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab. CT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints.

Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause.

The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared with placebo in two phase 3 randomized controlled trials. Its efficacy relative to available therapies is unknown. We conducted a systematic review and Bayesian network meta-analysis to compare efficacy with fezolinetant 45 mg and hormone therapy (HT) and non-HT for VMS in postmenopausal women. Using OvidSP, we systematically searched multiple databases for phase 3 or 4 randomized controlled trials in postmenopausal women with ≥7 moderate to severe VMS per day or ≥50 VMS per week published/presented in English through June 25, 2021. Mean change in frequency and severity of moderate to severe VMS from baseline to week 12 and proportion of women with ≥75% reduction in VMS frequency at week 12 were assessed using fixed-effect models. The network meta-analysis included data from the pooled phase 3 fezolinetant trials plus 23 comparator publications across the outcomes analyzed (frequency, 19 [34 regimens]; severity, 6 [7 regimens]; ≥75% response, 9 [15 regimens]). Changes in VMS frequency did not differ significantly between fezolinetant 45 mg and any of the 27 HT regimens studied. Fezolinetant 45 mg reduced the frequency of moderate to severe VMS events per day significantly more than all non-HTs evaluated: paroxetine 7.5 mg (mean difference [95% credible interval {CrI}], 1.66 [0.63-2.71]), desvenlafaxine 50 to 200 mg (mean differences [95% CrI], 1.12 [0.10-2.13] to 2.16 [0.90-3.40]), and gabapentin ER 1800 mg (mean difference [95% CrI], 1.63 [0.48-2.81]), and significantly more than placebo (mean difference, 2.78 [95% CrI], 1.93-3.62]). Tibolone 2.5 mg (the only HT regimen evaluable for severity) significantly reduced VMS severity compared with fezolinetant 45 mg. Fezolinetant 45 mg significantly reduced VMS severity compared with desvenlafaxine 50 mg and placebo and did not differ significantly from higher desvenlafaxine doses or gabapentin ER 1800 mg. For ≥75% responder rates, fezolinetant 45 mg was less effective than tibolone 2.5 mg (not available in the United States) and conjugated estrogens 0.625 mg/bazedoxifene 20 mg (available only as 0.45 mg/20 mg in the United States), did not differ significantly from other non-HT regimens studied and was superior to desvenlafaxine 50 mg and placebo. The only HT regimens that showed significantly greater efficacy than fezolinetant 45 mg on any of the outcomes analyzed are not available in the United States. Fezolinetant 45 mg once daily was statistically significantly more effective than other non-HTs in reducing the frequency of moderate to severe VMS. These findings may inform decision making with regard to the individualized management of bothersome VMS due to menopause.

Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant

BackgroundThe phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2− ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population.MethodsPostmenopausal patients with HR+/HER2− ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan–Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615).ResultsAt data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50–0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed.ConclusionsThis analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2− ABC.

An Integrative Study on the Inhibition of Bone Loss via Osteo-F Based on Network Pharmacology, Experimental Verification, and Clinical Trials in Postmenopausal Women.

The inhibition of bone loss remains a challenge for postmenopausal women, considering the fact that only three anabolic treatments for osteoporosis have been approved by the FDA. This study aimed to investigate the osteogenic capacities of Osteo-F, a newly developed herbal formula, upon integrating network analysis and pre-clinical studies into clinical trials. The network pharmacology analysis showed that a potential mechanism of Osteo-F is closely related to osteoblast differentiation. Consistent with the predicted mechanism, Osteo-F treatment significantly enhanced bone matrix formation and mineralization with collagen expression in osteoblasts. Simultaneously, secreted bone-forming molecules were upregulated by Osteo-F. After the administration of Osteo-F to osteoporotic mice, the femoral BMD and osteocalcin in the serum and bone tissues were significantly improved. Subsequently, a randomized, double-blinded, placebo-controlled clinical trial showed that 253 mg of Osteo-F supplementation for 24 weeks resulted in significant improvements in the Z-score and serum osteocalcin levels of postmenopausal women compared to the placebo, thus indicating bone anabolic efficacy. In the current study, the bone anabolic effect of Osteo-F was determined by activating the differentiation and mineralization of osteoblasts through integrating experiments based on network analysis into clinical trials, with synchronized, reliable evidence, demonstrating that Osteo-F is a novel bone anabolic treatment in postmenopausal women.

Effects of genistein aglycone in glucocorticoid induced osteoporosis: A randomized clinical trial in comparison with alendronate

Glucocorticoid-induced osteoporosis (GIO) complicates the clinical management of patients subjected to long-term glucocorticoid use. This study explored the effects of genistein on bone loss in a randomized double-blind alendronate-controlled trial in postmenopausal women with GIO. 200 postmenopausal women (taking at least 5 mg of prednisone equivalents) since 3 months, or more, and expected to continue for at least other 12 months, were randomized to receive genistein (54 mg/day daily) or alendronate (70 mg once a week) for 24 months. Both groups received also Calcium and Vitamin D3 supplementation. Median bone mineral density (BMD) at the antero-posterior lumbar spine significantly increased from 0.75 g/cm2 at baseline to 0.77 g/cm2 at 1 year and 0.79 g/cm2 at 2 years in alendronate-treated patients and from 0.77 g/cm2 at baseline to 0.79 g/cm2 at 12 months and to 0.80 g/cm2 at 24 months in genistein recipients. No difference was observed between the two treatments. Median BMD at the femoral neck increased from 0.67 g/cm2 at baseline to 0.68 g/cm2 at 1 year and 0.69 g/cm2 at 2 years in alendronate-treated patients and from 0.68 g/cm2 at baseline to 0.70 g/cm2 at 12 months and to 0.71 g/cm2 at 24 months in genistein recipients. No difference was observed between alendronate and genistein groups in BMD. Regarding bone markers genistein and alendronate statistically decreased c-terminal telopeptide, while osteocalcin, bone-ALP, and sclerostin showed greater changes in genistein treated patients. This randomized clinical trial suggests that genistein aglycone represents an additional therapeutic option for patients with GIO.

Effect of Lactobacillus Fermentum as a Probiotic Agent on Bone Health in Postmenopausal Women.

Probiotics are live microorganisms that confer health benefits on the host. Many animal studies have shown that among the probiotics, lactobacilli exert favorable effects on bone metabolism. Herein, we report the results of a randomized controlled trial performed to investigate the effect of Lactobacillus fermentum (L. fermentum) SRK414 on bone health in postmenopausal women. The bone turnover markers (BTMs) and bone mineral density (BMD) in participants in the study group (N=27; mean age, 58.4±3.4 years) and control group (N=26; mean age, 59.5±3.4 years) were compared during a 6-month trial. BTMs were measured at pretrial, 3 months post-trial, and 6 months post-trial, while BMD was measured at pre-trial and 6 months post-trial. Changes in the gut microorganisms were also evaluated. Femur neck BMD showed a significant increase at 6 months post-trial in the study group (P=0.030) but not in the control group. The control group showed a decrease in osteocalcin (OC) levels (P=0.028), whereas the levels in the study group were maintained during the trial period. The change in L. fermentum concentration was significantly correlated with that in OC levels (r=0.386, P=0.047) in the study group at 3 months post-trial. Probiotic (L. fermentum SRK414) supplementation was found to maintain OC levels and increase femur neck BMD during a 6-month trial in postmenopausal women. Further studies with a larger number of participants and a longer study period are required to increase the utility of probiotics as an alternative to osteoporosis medication.

Influence of food matrix delivery system on the bioavailability of vitamin D3: A randomized crossover trial in postmenopausal women

ObjectivesVitamin D insufficiency (blood 25-hydroxyvitamin D <50 nmol/L) is a global health problem. Vitamin D food fortification might be a solution, but knowledge is sparse on which food matrices yield the highest bioavailability. The aim of this study was to investigate the influence of different food matrices including complex formations with whey proteins on the human bioavailability of vitamin D. MethodsIn this randomized, multiple crossover trial, we enrolled 30 postmenopausal women 60 to 80 y of age with vitamin D insufficiency. We measured changes in serum concentrations of vitamin D3 (D3) postprandially for 24 h in response to the intake of 500 mL of different food matrices with 200 µg D3 added compared with a control (500 mL of water). Foods included apple juice with whey protein isolate (WPI), apple juice, semi-skim milk, and water (with D3). The food matrices were provided in a randomized order with ≥10-d washout period between them. On each intervention day, blood samples were collected at 0, 2, 4, 6, 8, 10, 12 and 24 h. ResultsD3 with WPI in juice did not enhance area under the curve (AUC) of serum D3 compared with juice without WPI (370 nmol × 24 h/L; 95% confidence interval [CI], 321–419 versus 357 nmol × 24 h/L; 95% CI, 308–406 nmol × 24 h/L; P = 0.65). However, compared with juice, the AUC was significantly higher in response to the intake of D3 in milk (452 nmol × 24 h/L; 95% CI, 402–502 nmol × 24 h/L) and water with D3 (479 nmol × 24 h/L; 95% CI, 430–527 nmol × 24 h/L; P < 0.05). No difference was observed between milk and water (P = 0.34). ConclusionsThe bioavailability of D3 was superior in milk and water compared with juice, regardless of whether WPI was added.

Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder.

Flibanserin treatment increases sexual desire and satisfying sexual events while decreasing distress in certain women diagnosed with acquired, generalized hypoactive sexual desire disorder (HSDD). Additional aspects of sexual function and the time course of response have not been fully characterized. To evaluate changes in sexual function assessed by the subdomains of the Female Sexual Function Index (FSFI) in women with HSDD treated with flibanserin. FSFI data pooled from 3 pivotal flibanserin trials in premenopausal women (flibanserin=1,165; placebo=1,203) and FSFI data from one complete flibanserin trial in postmenopausal women (flibanserin=432; placebo=463) were subjected to post-hoc analyses. For each FSFI subdomain, least squares mean change from baseline was calculated at each assessment visit (treatment weeks 4, 8, 16, 24) and treatment groups were compared using analysis of covariance. Standardized effect size (Cohen's d) was also determined for each FSFI subdomain. Changes from baseline in FSFI subdomains. Compared to placebo, both premenopausal (P < .02) and postmenopausal (P < .045) patients in the flibanserin group reported significantly greater increases over baseline in the FSFI subdomain scores of desire, arousal, lubrication, orgasm, and satisfaction. In premenopausal patients, significant improvements were observed at the first assessment of response (week 4) and were maintained through week 24. In postmenopausal patients, significant improvements were observed at week 4 for desire and arousal, while significant improvements in lubrication, orgasm, and satisfaction were observed at week 8. At week 24, excluding the pain subdomain, standardized effect sizes ranged from 0.18 to 0.28 in the premenopausal cohort and 0.12 to 0.29 in the postmenopausal cohort. In both pre- and postmenopausal patients, improvements in pain were smaller and largely undifferentiated between treatment groups. While variations in time to response should be taken into consideration, on average, the beneficial impact of flibanserin on overall sexual function occurs within the first month of treatment. The data also suggest that the response to flibanserin is sustained for the duration of treatment. Sexual function assessments were performed in a large cohort of 2,368 premenopausal women and 895 postmenopausal women. However, the FSFI assesses changes over a 1-month period and time points earlier than 4 weeks could not be assessed. These analyses suggest that assessment of benefit of flibanserin in HSDD should include improvements across all domains of sexual function, not only desire. Simon JA, Clayton AH, Goldstein I, et al. Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder. Sex Med 2022;10:100570.

Prunes preserve hip bone mineral density in a 12-month randomized controlled trial in postmenopausal women: the Prune Study

Dietary consumption of prunes has favorable impacts on bone health, but more research is necessary to improve upon study designs and refine our understandings. We evaluated the effects of prunes (50g or 100g/d) on bone mineral density (BMD) in postmenopausal women during a 12-mo dietary intervention. Secondary outcomes include effects on bone biomarkers. The single-center, parallel-arm 12-mo randomized controlled trial tested the effects of 50 g and 100 g prunes compared with a control group on BMD (every 6 mo) and bone biomarkers in postmenopausal women. In total, 235 women (age 62.1± 5.0y) were randomly allocated into control (n=78), 50-g prune (n=79), or 100-g prune (n=78) groups. Compliance was 90.2±1.8% and 87.1±2.1% in the 50-g and 100-g prune groups. Dropout was 22%; however, the dropout rate was 41% for the 100-g prune group (compared with other groups: 10%, control; 15%, 50g prune; P<0.001). A group×time interaction for total hip BMD was observed in control compared with 50-g prune groups (P<0.05) but not in control compared with 100-g prune groups (P>0.05). Total hip BMD decreased -1.1±0.2% in the control group at 12 mo, whereas the 50-g prune group preserved BMD (-0.3±0.2%) at 12 mo (P<0.05). Although hip fracture risk (FRAX) worsened in the control group at 6 mo compared with baseline (10.3±0.5% compared with 9.8±0.5%, P<0.05), FRAX score was maintained in the pooled (50 g+100g) prune groups. A 50-g daily dose of prunes can prevent loss of total hip BMD in postmenopausal women after 6 mo, which persisted for 12 mo. Given that there was high compliance and retention at the 50-g dosage over 12 mo, we propose that the 50-g dose represents a valuable nonpharmacologic treatment strategy that can be used to preserve hip BMD in postmenopausal women and possibly reduce hip fracture risk. This trial was registered at clinicaltrials.gov as NCT02822378.

The Diurnal Blood Metabolome and Effects of Vitamin D Supplementation: A Randomised Crossover Trial in Postmenopausal Women.

A way to maintain an adequate vitamin D status is through supplementation. Demonstration of blood-metabolome rhythmicity of vitamin D3 post-dosing effects is lacking in the pharmaco-metabonomics area. Thus, the overall aim of this study was to investigate the diurnal changes in the blood metabolome and how these are affected by vitamin D3 supplementation. The study was conducted as a crossover study, and the treatment included 200 µg (8000 IU) of vitamin D3 as compared with placebo with a washout period of at least 10 days. The participants were postmenopausal women aged 60–80 years (N = 29) with vitamin D insufficiency (serum 25-hydroxyvitamin D < 50 nmol/L) but otherwise healthy. During the intervention day, blood samples were taken at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h, and plasma was analysed by proton nuclear magnetic resonance (NMR) spectroscopy as a metabolomics approach. In general, diurnal effects were identified for the majority of the 20 quantified metabolites, and hierarchical cluster analysis revealed a change in the overall plasma metabolome around 12 AM (6 h after intervention), suggesting that the diurnal rhythm is reflected in two diurnal plasma metabolomes; a morning metabolome (8–12 AM) and an afternoon/evening metabolome (2–8 PM). Overall, the effect of vitamin D supplementation on the blood metabolome was minor, with no effect on the diurnal rhythm. However, a significant effect of the vitamin D supplementation on plasma acetone levels was identified. Collectively, our findings reveal an influence of diurnal rhythm on the plasma metabolome, while vitamin D supplementation appears to have minor influence on fluctuations in the plasma metabolome.

At-risk patient and healthcare provider perspectives on clinical trial participation for ductal carcinoma in situ.

10539 Background: Significant challenges exist in recruiting newly diagnosed ductal carcinoma in situ (DCIS) patients to participate in presurgical intervention trials. Perceived motivators and barriers to participation have not been formally studied from the patient or healthcare provider (HCP) perspective. Based on our experience in the Promise Study (NCT02694809), we hypothesized that delaying surgery and concern for side effects are barriers to trial participation and that access to new treatments and financial benefits are motivators. To improve recruitment, we conducted focus groups to better understand barriers and motivators for trial participation in our patient population. Methods: Three focus groups with post-menopausal women (PMW) without history of DCIS, one focus group with patients previously treated for DCIS, and two HCP focus groups were conducted. Due to COVID-19, the focus groups took place online via videoconferencing and included participants from across the United States. A third-party facilitator generated discussion on predetermined topics including knowledge of DCIS, clinical trial recruitment materials, hormone replacement therapy, healthcare delivery and clinical trials during COVID-19, and perceived motivators and barriers to trial participation in general and specifically for women with DCIS. Here, we focus on comparing perceived influential factors for patient participation in DCIS clinical trials in PMW and HCP focus groups. Qualitative thematic analysis was completed on focus group transcripts in NVivo. Results: PMW had no knowledge of DCIS prior to the focus groups and believed DCIS should be removed promptly. PMW believed barriers to DCIS clinical trial participation included the potential for the study drug to cause harm, distrust of medicine, and the fact that DCIS is not life-threatening. PMW identified helping future DCIS patients, accessing better treatment, and easing anxiety as motivators for DCIS trial participation. HCPs believed patients were motivated by increased monitoring by the medical team, financial incentive, and access to newer treatment. HCPs believed that delays in DCIS surgery, the potential for the intervention to be harmful or ineffective, and the trial causing patient anxiety were barriers. Neither group emphasized time commitment as a barrier to DCIS trial participation. PMW were not motivated by financial incentives. Conclusions: Knowledge about DCIS is lacking in PMW. PMW and HCPs agreed that the risk of harm caused by study interventions is a deterrent to trial participation and that access to superior treatment is a motivator. However, PMW and HCPs did not agree on other motivators and barriers which could lead to missed recruitment opportunities. Providing educational materials on DCIS and addressing motivators and barriers to clinical trial participation may increase recruitment to presurgical DCIS trials. Clinical trial information: NCT02694809.

Abstract PD15-02: HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

Abstract Background: Approximately 10% of estrogen receptor positive (ER+) early breast cancers (EBC) are human epidermal growth factor positive/overexpressed (HER2+). Resistance to aromatase inhibitors (AIs) is poorly understood among ER+HER2+ BC. We aimed to identify biomarkers of response and resistance using the HER2+ tumours in the POETIC trial. Methods: POETIC was a phase III trial of post-menopausal women with ER+ EBC randomized 2:1 to 2-weeks of peri-surgical AI vs control, followed by standard-of-care. Baseline formalin-fixed paraffin-embedded samples from 342 ER+HER2+ BC (237 treated/105 controls) were gene expression profiled using Breast cancer 360™ panel (NanoString) covering intrinsic subtypes and 40 key biological signatures. New molecular subgroups were identified using consensus clustering (CC).Proliferation rate was estimated as percentage of cancer-cells staining for Ki67. Ki67 response was defined by percentage-changes from baseline to surgery: poor (PR; reduction &amp;lt;50%), intermediate (IR; 50-75%) and good (GR; &amp;gt;75%). Residual Ki67 at 2 weeks timepoint (Ki672w) was defined as High (H) (≥ 10%) vs Low (L) (&amp;lt;10%). Association of molecular features with Ki67 response was assessed using logistic regression models and with time to recurrence (TTR) using multivariable Cox regression models adjusted for post-surgery clinicopathological variables: grade, tumour size, nodal status and age. Results: Ki672w was measured for all treated samples (n = 227, 48% H, 52% L) and a fraction of controls (n = 50, 96% H, 4% L). At baseline, 45% of tumours were HER2-enriched (HER2-E), 53% Luminal A/B and 2% Basal-Like. HER2-E associated with high Ki672W (84% H, 16% L) compared to non-HER2-E (29% H, 71% L, p&amp;lt;0.001). Amongst the 40 BC360 signatures, 9 were significantly associated with Ki67 response (Table). High expression of endocrine-related and apoptosis signatures associated with GR while HRD and TP53 with PR. These features were also related to Ki672W, with additional signatures involved in immune-checkpoint component and immune-enrichment (IM) (IDO1, PD-L1, IFN-gamma and T-reg) associated with high Ki672W.. Using CC, 4 molecular subgroups predicting differential response to AI were identified. Cluster (C) 1 was characterized by overexpression of IM features and low ER signaling (42%); C2 low IM but highest ERBB2 expression (15%); C3 ESR1 high and PgR low (4%) and C4 high endocrine signaling and lowest ERBB2 expression (39%). Distribution of Intrinsic subtypes varied across these molecular subgroups with the majority of C1 being HER2-E (62%) and Luminal B (27%); C2 HER2-E (74%); C3 Luminal B (64%) and C4 Luminal B (55%) and Luminal A (30%). HER2-E had significantly poorer TTR (HR 2.14; 95%CI1.11-4.17; p=0.0224) compared to Luminal tumours, remaining significant (HR 2.55, 95%CI1.14-5.69; p=0.0222) in the multivariable analysis. C2 (HR 4.67, 95%CI 1.90-11.51; p&amp;lt;0.001) and C4 (HR 2.42, 95%CI1.05-4.5.58; p=0.0385) were independent predictors of shorter TTR compared to C1, adding significant value beyond intrinsic subtypes (Likelihood ratio test, p=0.00429). Conclusions: Our results confirm that HER2-E, TP53 mutation, HRD and IM features are the main components driving poor early response to AI in ER+/HER2+ EBC. Novel molecular subgroups identify additional non-HER-E tumours not responding to AI with an increased risk of relapse. The appropriate additional treatment warrants further investigation. List of significant gene expression signatures associated with response as defined by reduction of Ki67. Odds ratio (OR) were determined by ordinal logistic regression analyses. OR: &amp;lt;1 indicating associated with good response and &amp;gt; 1.0 associated with worse response.Odds Ratiop-valuep-adjusted (False Discovery Rate)ESR10.65&amp;lt; 0.001&amp;lt; 0.001Estrogen Receptor Signaling0.44&amp;lt; 0.001&amp;lt; 0.001ERBB21.52&amp;lt; 0.001&amp;lt; 0.001TP53 mutant signature2.65&amp;lt; 0.001&amp;lt; 0.001FOXA10.42&amp;lt; 0.001&amp;lt; 0.001Apoptosis0.26&amp;lt; 0.0010.00228Homologous Recombination Deficiency (HRD)2.33&amp;lt; 0.0010.00349PgR0.820.001480.00737Hypoxia2.180.001660.00737 Citation Format: Milana A Bergamino Sirvén, Elena López-Knowles, Gabriele Morani, Holly Tovey, Lucy Kilburn, Chris Holcombe, Anthony Skene, Ian Smith, John Robertson, Gene Schuster, Judith M Bliss, Mitch Dowsett, Maggie CU Cheang, POETIC investigators. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer [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 PD15-02.

Abstract PD2-07: Impact of using cross-platform gene expression profiling technologies and computational methods for intrinsic breast cancer subtyping in PALOMA-2 and PALLET

Abstract Background Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients (pts) with breast cancer (BC) treated with chemotherapy, human epidermal growth factor receptor 2 (HER2) targeted therapies, and endocrine therapies (ETs). Classifying tumors into intrinsic subtypes to determine optimal treatment is often applied using PAM50, commercially known as Prosigna. Meanwhile, Absolute Assignment of Breast Cancer Intrinsic Molecular Subtypes (AIMS) computational method was trained to predict PAM50-based IBCMS. As the PAM50 algorithm was developed to capture the major subtypes in a general pt population, clinicopathologic distribution of the study cohort and technology platform calibration should be considered in IBCMS analyses. This study compared different next-generation sequencing technologies and methodologic approaches of PAM50 on tumor samples from 2 randomized trials of postmenopausal women with estrogen receptor-positive (ER+)/HER2-negative (HER2-) BC. Methods PALOMA-2 is a double-blind, randomized study of first-line palbociclib (PAL) + letrozole (LET) for ER+/HER2- advanced BC (ABC). Tumor samples from consented pts were subtyped using the validated RUO PAM50 assay (ruoProsigna, NanoString); results were compared with published subtype results using AIMS on EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics). PALLET is a phase 2, randomized trial of PAL+LET as neoadjuvant therapy in pts with ER+ HER2- BC. Baseline frozen tumor biopsies underwent whole transcriptome mRNA-sequencing (mRNA-seq). IBCMS was performed using AIMS; PAM50 subtyping was performed on data normalised with subgroup-specific gene centering and microarray-RNA-sequencing calibration. Results In PALOMA-2, 222 pts had both ruoProsigna and AIMS data; an overall 54% agreement rate between methods was observed, with 46% (56/121) of Luminal B (LumB) subtype by ruoProsigna assigned as Luminal A (LumA) by AIMS and 67% (6/9) of basal-like by ruoProsigna as HER2-enriched (HER2-E) by AIMS (Table 1). In PALLET, 224 pts had mRNA-seq data; a 69% agreement between the two approaches (AIMS and PAM50) was observed, with only 4% (2/49) of LumB assigned as LumA by AIMS but 17% (26/156) and 16% (25/156) of LumA considered LumB or normal-like by AIMS, respectively. Progression-free survival (PFS) by ruoProsigna-derived subtype in PALOMA-2 showed that PAL+LET benefited all pts but those with a basal-like subtype (Table 2). With AIMS, PAL+LET provided a PFS benefit in pts with LumA and LumB subtypes, but was less effective in the HER2-E subtype. Conclusion Intrinsic subtyping has potential clinical utility. PAL+ET should be considered for ER+/HER2- ABC, except possibly in pts with a basal-like tumor, consistent with previous reports. A standardized clinical PAM50 assay and bioinformatics approach should be used as discrepancies in gene expression platforms and algorithms lead to different results and could misguide treatment decisions. Clinical trial identification: Pfizer (NCT01740427) Table 1.Intrinsic Subtyping by IBCMS MethodsPALOMA-2PALLETMethodruoProsignaPAM50 mRNAseqAIMS BasalHER2LumALumBGrand TotalBasalHER2LumALumBNormalGrand TotalBasal-like, n (%)1 (11)NANANA13 (75)0001 (8)4HER2-E, n (%)6 (67)6 (30)6 (8)13 (10)311 (25)3 (100)8 (5)6 (12)1 (8)19LumA, n (%)NA2 (10)60 (83)56 (46)1180097 (62)2 (4)099LumB, n (%)2 (22)12 (60)3 (4)52 (43)690026 (17)41 (84)067Normal-like, n (%)NANA3 (4)NA30025 (16)010 (83)35Grand Total9 (100)20 (100)72 (100)121 (100)2224 (100)3 (100)156 (100)49 (100)12 (100)224NA=Not available Table 2.Median PFS statistics by subtype in PALOMA-2PAL+LET PFS, monthsPBO+LET PFS, monthsHazard Ratio(95% CI)P ValueruoProsignaBasal-like8.2 (n=5)3.6 (n=4)0.39 (0.09-1.77)0.206HER2-E11.0 (n=12)5.1 (n=8)0.41 (0.15-1.11)0.071LumA37.2 (n=52)13.6 (n=20)0.42 (0.21-0.84)0.011LumB27.6 (n=79)13.8 (n=42)0.63 (0.40-1.00)0.049AIMSBasal-likeNANANANAHER2-E16.4 (n=21)8.4 (n=10)0.82 (0.32-2.1)0.684LumA30.6 (n=84)16.5 (n=34)0.56 (0.33-0.95)0.029LumB19.3 (n=41)8.8 (n=28)0.39 (0.23-0.67)&amp;lt;0.001NA=Not available; PBO=placebo Citation Format: Maggie Cheang, Mitch Dowsett, Mothaffar Rimawi, Stephen Johnston, Samuel Jacobs, Judith Bliss, Katherine Pogue-Geile, Lucy Kilburn, Zhou Zhu, Eugene F. Schuster, Hui Xiao, Lisa Swaim, Shibing Deng, Dongrui R. Lu, Eric Gauthier, Jennifer Tursi, Dennis J. Slamon, Hope S. Rugo, Richard S. Finn, Yuan Liu. Impact of using cross-platform gene expression profiling technologies and computational methods for intrinsic breast cancer subtyping in PALOMA-2 and PALLET [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 PD2-07.

The acute effects of milk intake on calcium homeostasis and cardiovascular outcome: A randomized crossover trial in postmenopausal women.

ObjectiveThe importance of calcium intake from dairy in regard to cardiovascular health has been investigated in several studies with discrepant results. Hence, we aim to investigate the immediate effects of milk intake on cardiovascular function.DesignA randomized crossover study with at least 10 days for washout between the two interventions, 500 ml of water with 200 µg of cholecalciferol or 500 ml of semi‐skimmed milk containing approximately 600 mg of calcium with 200 µg of cholecalciferol.PatientsTwenty community‐based postmenopausal women aged 60–80 years.MeasurementsParathyroid hormone and ionized calcium were measured at baseline and after 2 and 4 h on each study day. Pulse wave analysis and velocity were measured at baseline and after 4 h on each study day.ResultsCompared to water, milk intake increased ionized calcium levels by 0.02 mmol/L (p = .029) and decreased parathyroid hormone levels by 1.78 pmol/L (p < .001). The two interventions caused no changes as measured 4 h after the intervention in the following indices of cardiovascular health; pulse wave velocity, brachial diastolic or systolic blood pressure, central diastolic or systolic blood pressure, mean arterial pressure, pulse pressure, augmentation pressure, augmentation index, heart rate or pulse transit time.ConclusionsDespite significant changes in calcium homeostasis with increased levels of ionized calcium following milk intake, no acute effects seem to occur on measures of cardiovascular health.

The acute effects of milk intake on calcium homeostasis and cardiovascular outcome: A randomized, crossover trial in postmenopausal women

OBJECTIVE The importance of calcium intake from dairy in regard to cardiovascular health has been investigated in several studies with discrepant results. Hence, we aim to investigate the immediate effects of milk intake on cardiovascular function. DESIGN A randomized crossover study with at least 10 days for washout between the two interventions, 500 ml of water with 200 µg of cholecalciferol or 500 ml of semi-skimmed milk containing approximately 600 mg of calcium with 200 µg of cholecalciferol. PATIENTS Twenty community-based postmenopausal women aged 60-80 years. MEASUREMENTS Parathyroid hormone and ionized calcium were measured at baseline and after 2 and 4 h on each study day. Pulse wave analysis and velocity were measured at baseline and after 4 h on each study day. RESULTS Compared to water, milk intake increased ionized calcium levels by 0.02 mmol/L (p = .029) and decreased parathyroid hormone levels by 1.78 pmol/L (p < .001). The two interventions caused no changes as measured 4 h after the intervention in the following indices of cardiovascular health; pulse wave velocity, brachial diastolic or systolic blood pressure, central diastolic or systolic blood pressure, mean arterial pressure, pulse pressure, augmentation pressure, augmentation index, heart rate or pulse transit time. CONCLUSIONS Despite significant changes in calcium homeostasis with increased levels of ionized calcium following milk intake, no acute effects seem to occur on measures of cardiovascular health.

Obesity Does Not Interfere with the Cholesterol-Lowering Effect of Plant Stanol Ester Consumption (as Part of a Heart-Healthy Diet).

Dietary modifications including plant stanol ester consumption are recommended measures to control serum and low-density lipoprotein (LDL)-cholesterol concentrations, but obesity can affect their responses. We investigated whether body mass index (BMI) affects serum cholesterol levels during plant stanol (mainly sitostanol) ester consumption. This ad hoc analysis was based on earlier results of a cross-over, randomized controlled trial of postmenopausal women consuming rapeseed oil-based margarine without or with plant stanol ester (3 g plant stanols/day) for seven weeks. We classified the subjects as normal-weight (BMI ≤ 25 kg/m2, n = 9, mean 22.6 kg/m2) or overweight/obese (BMI > 25 kg/m2, n = 11, mean 28.4 kg/m2), and recalculated the results, focusing on cholesterol absorption, cholesterol synthesis, and fecal steroid outputs. Serum cholesterol levels were similar in the groups during the control diet. Plant stanol ester reduced serum cholesterol by 0.63 ± 0.19 mmol/L (11%) in normal-weight and by 0.75 ± 0.13 mmol/L (12%) in overweight/obese subjects (p < 0.05 for both), and cholesterol absorption was reduced in both groups. However, relative and dietary cholesterol absorption were more effectively reduced in normal-weight subjects. In conclusion, overweight/obesity did not interfere with the serum cholesterol response to plant stanol ester consumption despite substantial differences in cholesterol metabolism between the groups.

Cardiovascular Safety and Sclerostin Inhibition.

Sclerostin, which is primarily produced by the osteocytes, inhibits the canonical Wnt pathway and thereby the osteoblasts and stimulates RANKL release by the osteocytes and thereby osteoclast recruitment. Inhibition of sclerostin therefore causes stimulation of bone formation and inhibition of resorption. In clinical trials, romosozumab, an antibody against sclerostin, increases bone mineral density and reduces the risk of fractures compared with placebo and alendronate. The cardiovascular safety of romosozumab was adjudicated in 2 large clinical osteoporosis trials in postmenopausal women. Compared with placebo, the incidence of cardiovascular events was similar in the 2 treatment groups. Compared with alendronate, the incidence of serious cardiovascular events was higher in women treated with romosozumab. The incidence of serious cardiovascular adverse events was low and post hoc analyses should therefore be interpreted with caution; however, the relative risk seemed unaffected by preexisting cardiovascular disease or risk factors. Sclerostin is expressed in the vasculature, predominantly in vascular smooth muscle cells in the media. However, preclinical and genetic studies have not demonstrated any increased cardiovascular risk with continuously low sclerostin levels or inhibition of sclerostin. Furthermore, no potential mechanisms for such an effect have been identified. In conclusion, while there is no preclinical or genetic evidence of a harmful effect of sclerostin inhibition on cardiovascular safety, the evidence from the large clinical trials in postmenopausal women is conflicting. Romosozumab should therefore be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.

Inflammatory marker changes in a 24-month dietary and physical activity randomised intervention trial in postmenopausal women

Chronic low-grade inflammation plays a role in the pathogenesis of several chronic diseases including cancer. Physical activity (PA) and diet have been supposed to modulate inflammatory markers. We evaluated the effects of a 24-month dietary and/or PA intervention on plasma levels of pro-inflammatory cytokines, a secondary analysis in the DAMA factorial trial. The 234 study participants (healthy postmenopausal women with high breast density, 50–69 years, non smokers, no hormone therapy) were randomised to four arms: (1) isocaloric dietary intervention mainly based on plant-foods; (2) moderate-intensity PA intervention with at least 1 h/week of supervised strenuous activity; (3) both interventions; (4) general recommendations on healthy dietary and PA patterns. Interleukins (IL)-1α, -1β, -6, tumor necrosis factor-α and C-reactive protein were measured at baseline and at the end of the intervention. Intention-to-treat-analyses were carried out using Tobit regression. Although all cytokines tended to increase over time, after 24 months women in the PA intervention (arms 2 + 3) showed lower levels of IL-1α (exp(β) = 0.66; p = 0.04) and IL-6 (exp(β) = 0.70; p = 0.01) in comparison with women in the control group (arms 1 + 4). No effects of the dietary intervention emerged. In healthy postmenopausal women with high breast density a moderate-intensity PA appears to slow the age-related increase of pro-inflammatory cytokines.

A new approach to prevent cervical stenosis in postmenopausal women after loop electrosurgical excision procedure: a randomized controlled trial

To determine whether regular cervical dilatation is effective for preventing cervical stenosis, and to identify the associated risk factors, in postmenopausal women after LEEP. This was a prospective randomized clinical trial in postmenopausal women who underwent LEEP at our hospital between August 2018 and May 2019. Patients who met the study criteria were randomly allocated to three groups: control group (without any intervention), intervention group A (underwent cervical dilatation at the 3rd, 5th, and 8th week after LEEP) and intervention group B (underwent cervical dilatation at the 4th, 8th, and 12th week after LEEP). A colposcopic follow-up examination was conducted at 6 months after LEEP to determine the incidence of cervical stenosis. A total of 404 postmenopausal women were found to be finally eligible for the study. The rate of cervical stenosis in the control group was significantly higher than that in the intervention group, and the rate in group A was significantly lower than that in group B. We found regular dilatation after LEEP in postmenopausal women can prevent cervical stenosis. Further, the 3rd, 5th, and 8th weeks after LEEP are optimal time points. Finally, LEEP frequency and resection depth are significant risk factors and can be used to screen postmenopausal women at risk for cervical stenosis after LEEP.

Abstract P5-01-05: Genomic alterations detected by circulating tumor DNA and correlation with response to treatment with elacestrant, an oral selective estrogen receptor degrader, in phase 1 trials in postmenopausal women with ER+/HER2- advanced/metastatic breast cancer

Abstract Background: ER+ metastatic breast cancer (mBC) remains a clinical challenge as most patients (pts) eventually have disease progression on treatment (tx). Multiple molecular mechanisms of resistance to standard-of-care drugs have been reported including mutations in ESR1 (mESR1) or PIK3CA (mPIK3CA); understanding how these affect response to subsequent tx is important. Elacestrant (RAD1901), an investigational oral selective estrogen receptor degrader (SERD), has demonstrated preclinical efficacy in pt-derived xenograft models of ER+ BC, including models harboring mESR1 and mPIK3CA. Elacestrant was evaluated in 2 phase 1 clinical trials (NCT02650817, NCT02338349) in postmenopausal women with ER+/HER2- mBC, including pts that had received multiple prior endocrine tx (median=3) and targeted tx, including CDK4/6 inhibitors (38%). Circulating tumor DNA (ctDNA) collected in these 2 trials was used to characterize the molecular features of this heavily pretreated population and correlate them with elacestrant response. Methods: ctDNA samples were collected at baseline (BL), on-tx (OT) and end-of-tx (EOT). BL samples were analyzed using the Guardant360® assay (Guardant Health) to detect genomic alterations in 73 relevant genes. Changes in BL mESR1 allele frequency of 12 single nucleotide variants (SNVs) in the ligand binding domain of ESR1 were assessed in paired OT and EOT ctDNA samples using the OncoBEAM™ platform (Sysmex Inostics). Response was assessed using RECIST v1.1. Results: Among 73 pts enrolled in these 2 trials, 57 had BL samples. At least 1 alteration was detected in 93% (n=53) of pt samples, with alterations detected in 52 of the 73 genes in the Guardant360® panel. The most frequently detected BL alterations were in ESR1 (47%) and PIK3CA (44%), with alterations in both genes observed in 21% of pts. At BL, 25% (14/57) of pt samples had &amp;gt;1 mESR1; the most commonly detected mESR1 were Y537S (56%), D538G (56%), and Y537N (26%). Following elacestrant tx, there was a decrease in mESR1 allele frequency in 100% of samples (11/11 mESR1 SNVs decreased OT in 9/9 pts). In paired EOT samples from pts lacking mESR1 at BL analyzed to date (N=23), 1 new mESR1 was detected in 1 pt. Among response-evaluable (RE) pts with mESR1 at BL (n=16), there were 4 partial responses (PR; 25%); clinical benefit rate (CBR) at 24 weeks (ie, stable disease + PR) in clinical benefit evaluable (CBE) pts was 52% (11/21); and median progression-free survival (mPFS) in intention-to-treat (ITT) pts was 8.6 mo. Among RE pts with mPIK3CA at BL (n=16), there were 2 PRs (13%); CBR at 24 weeks in CBE pts was 24% (5/21); and mPFS (ITT pts) was 1.9 mo. Conclusions: Relevant genomic alterations, especially in ESR1 and PI3KCA, were detected at BL in a significant proportion of heavily pretreated postmenopausal women with ER+/HER2- mBC enrolled in elacestrant phase 1 trials. Clinical benefit, including PR, was observed in pts with genomic alterations, including mESR1 and PIK3CA. Elacestrant monotherapy vs. standard of care endocrine tx is currently being studied in the phase 3 “EMERALD” study in ER+/HER2- mBC pts, including pts with mESR1, who have received 1 or 2 prior lines of endocrine tx and prior CDK4/6i (NCT03778931). Citation Format: Teeru Bihani, JungAh Jung, Hitisha K Patel, Aditya Bardia, Peter Kabos, Virginia Kaklamani, Agnes Jager, Philippe Aftimos, Sharon Wilks, Elisabeth de Vries, Wael Harb, Donald Richards, Amy Weise, Robert Wesolowski, Catharina CW Menke-van der Houven van Oordt, Paul Conkling, Patrick Neven, Maureen G Conlan. Genomic alterations detected by circulating tumor DNA and correlation with response to treatment with elacestrant, an oral selective estrogen receptor degrader, in phase 1 trials in postmenopausal women with ER+/HER2- advanced/metastatic breast cancer [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 P5-01-05.