Severe Vasomotor Symptoms Research Articles

Using machine learning to predict individual patient toxicities from cancer treatments

PurposeMachine learning (ML) is a powerful tool for interrogating datasets and learning relationships between multiple variables. We utilized a ML model to identify those early breast cancer (EBC) patients at highest risk of developing severe vasomotor symptoms (VMS).MethodsA gradient boosted decision model utilizing cross-sectional survey data from 360 EBC patients was created. Seventeen patient- and treatment-specific variables were considered in the model. The outcome variable was based on the Hot Flush Night Sweats (HFNS) Problem Rating Score, and individual scores were dichotomized around the median to indicate individuals with high and low problem scores. Model accuracy was assessed using the area under the receiver operating curve, and conditional partial dependence plots were constructed to illustrate relationships between variables and the outcome of interest.ResultsThe model area under the ROC curve was 0.731 (SD 0.074). The most important variables in the model were as follows: the number of hot flashes per week, age, the prescription, or use of drug interventions to manage VMS, whether patients were asked about VMS in routine follow-up visits, and the presence or absence of changes to breast cancer treatments due to VMS. A threshold of 17 hot flashes per week was identified as being more predictive of severe VMS. Patients between the ages of 49 and 63 were more likely to report severe symptoms.ConclusionMachine learning is a unique tool for predicting severe VMS. The use of ML to assess other treatment-related toxicities and their management requires further study.

General and Central Obesity Are Associated With Increased Severity of the VMS and Sexual Symptoms of Menopause Among Chinese Women: A Longitudinal Study.

BackgroundStrong evidence has linked overweight and obesity to increased risks of cardiovascular disease and all-cause mortality in Chinese populations. Menopause is considered associated with increased obesity and central body fat distribution. However, the correlation between obesity and menopausal symptoms has not been well studied.ObjectiveTo examine the associations between obesity or abdominal obesity and menopausal symptoms as women progressed from premenopausal to postmenopausal status.DesignThis study included 430 midlife Chinese women who had experienced natural menopause and were followed up for 10 years. Physical examinations and questionnaires should be completed annually. The questionnaires include the Menopause-Specific Quality of Life questionnaire, the Hospital Anxiety and Depression Scale, and other physical and behavioral factors.ResultsAmong women who were not obese (n=345) or not abdominal obese (n=372) at baseline, 5.8% and 31.7% became obese or abdominal obese at the recent follow-up visit, respectively. Women at the recent follow-up visit had an increased body mass index (BMI) by 0.14%, and the waist-to-hip ratio (WHR) increased by 5.2% compared with the data at baseline. In multivariate analysis, more frequent hot flashes, moderate/severe bothered vasomotor symptoms (VMS), mild bothered sexual functioning, and less anxiety symptoms were significantly associated with obesity. Increasing age, moderate/severe bothered VMS, and less anxiety symptoms were independently associated with abdominal obesity. Multivariable analysis also showed that less education level is independently associated with both obesity and abdominal obesity.ConclusionOur findings suggest that the proportion of obesity and abdominal obesity increased gradually during menopause. The increase of abdominal obesity is more rapidly than obesity in middle-aged women. Both obesity and abdominal obesity are related with severe or frequent VMS and anxiety symptoms in Chinese women. Although the proportion of obese women in China is lower than in western countries, the problem of abdominal obesity and related complications cannot be ignored.

657. Do personality traits affect the perceived severity of menopausal symptoms in postmenopausal women?

Introduction and aims of the study: To investigate the association of personality traits with the severity of vasomotor symptoms (VMS) in a predominantly Greek population. Methods: A questionnaire-based study of women from the Menopause Clinic of a University Hospital in Athens, Greece. Sociodemographic parameters were documented through a structured interview. All women were asked to complete the Menopause Rating Scale (MRS) for the assessment of severity of menopausal symptoms, the Hot Flush Belief (HFB) for the assessment of how women were coping with their symptoms and the Big Five Inventory questionnaires for the assessment of personality traits.

A Clinical Review on Paroxetine and Emerging Therapies for the Treatment of Vasomotor Symptoms.

Most women experience vasomotor symptoms (VMS) during their menopausal transition. Menopausal hormone therapy (HT) is the most effective treatment for VMS, but some women choose not to use HT or have contraindications to using HT. Non-hormonal treatment options should be offered to these symptomatic menopausal women. Multiple large randomized controlled trials have demonstrated statistically significant reductions in hot flash severity and/or frequency with the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). To date, paroxetine mesylate remains the only non-hormonal treatment that has been approved by the United States Food and Drug Administration (FDA) for the management of moderate to severe postmenopausal vasomotor symptoms. Lower doses are needed to reduce VMS than those used to treat anxiety or depression, which is beneficial since side effects are typically dose dependent. The recommended dosage is 7.5 mg once daily at bedtime. Dose dependent side effects include nausea, fatigue, and dizziness. Knowing potential medication interactions is critical such as with medications that can lead to serotonin syndrome, concomitant use with monoamine oxidase inhibitors and being aware of p450 drug metabolism is essential for patients taking drugs that utilize the CYP2D6 enzyme for metabolism including tamoxifen. This review discusses in detail the available data supporting the use of paroxetine for the treatment of VMS, including side effects and considerations regarding prescribing. A discussion of other emerging treatments is included as well, including estetrol, oxybutynin and neurokinin 3 (NK3) receptor antagonists.

Prevalence, severity, and associated factors in women in East Asia with moderate-to-severe vasomotor symptoms associated with menopause.

Objective:To understand prevalence, severity, impact, and treatment of vasomotor symptoms associated with menopause, using cross-sectional survey data.Methods:This online, two-part survey was conducted in East Asia among women 40-65 years recruited from established online panels (Edelman, Beijing; Hankook Research, Seoul; Rakuten Insight, Taipei) using stratified sampling. Part I collected demographics/disease characteristics, including menopausal status and vasomotor symptom severity. Women with moderate-to-severe vasomotor symptoms completed Part II, including clinical characteristics, health-related quality of life, and healthcare-seeking behavior. Primary endpoints included vasomotor symptom prevalence and severity and proportions of women eligible and willing to take hormone therapy. Results are presented for each of the three online panels separately and as a pooled total. All analyses are descriptive with no formal hypothesis testing across groups.Results:Numbers of peri- versus postmenopausal women completing Part I were Edelman, 1,588 (55.1% vs 44.9%); Hankook Research, 1,000 (43.6% vs 56.4%); Rakuten Insight, 773 (61.7% vs 38.3%). Vasomotor symptom prevalence was =80% in each region; overall moderate-to-severe vasomotor symptom prevalence was 55%; >50% of women were untreated. Most of those treated used non-prescription treatments. Menopausal hormone therapy use was reported by 11.6% of peri- and 7.2% of postmenopausal women. In peri- and postmenopausal women with moderate-to-severe vasomotor symptoms, 8.6% and 3.4%, respectively, were hormone therapy-willing, 19.3% and 16.8% hormone therapy-contraindicated, 25.4% and 23.0% hormone therapy-cautious, and 10.2% and 8.3% hormone therapy-averse. Women experienced significant burden on health-related quality of life and substantial impairment of work productivity and daily activities.Conclusions:Vasomotor symptoms associated with menopause affected =80% of women aged 40 to 65 years. A substantial proportion of women are unsuitable for, or choose not to take, menopausal hormone therapy, resulting in an unmet need for nonhormonal treatment options.

Vasomotor symptoms in early breast cancer-a "real world" exploration of the patient experience.

BackgroundDespite the frequency of vasomotor symptoms (VMS) in patients with early breast cancer (EBC), their optimal management remains unknown. A patient survey was performed to determine perspectives on this important clinical challenge.MethodsPatients with EBC experiencing VMS participated in an anonymous survey. Patients reported on the frequency and severity of VMS using the validated Hot Flush Rating Scale (HFRS) and ranked their most bothersome symptoms. Respondents were also asked to determine endpoints that defined effective treatment of VMS and report on the effectiveness of previously tried interventions.ResultsResponses were received from 373 patients, median age 56 years (range 23–83), who experienced an average of 5.0 hot flashes per day (SD 6.57). Patients reported the most bothersome symptoms to be feeling hot/sweating (155/316, 49%) and sleeping difficulties (86/316, 27%). Fifty-five percent (201/365) of patients would consider a treatment to be effective if it reduced night-time awakenings. While 68% of respondents were interested in trying interventions from their healthcare team to manage VMS, only 18% actually did so. Of the 137 patients who had tried an intervention for VMS, pharmacological treatments, exercise, and relaxation strategies were more likely to be effective, while therapies such as melatonin and black cohosh were deemed less effective.ConclusionVMS are a common and bothersome problem for EBC patients, with a minority receiving interventions to manage these symptoms. Further research is needed to identify patient-centered strategies for managing these distressing symptoms.

Vasomotor symptoms and carotid artery intima-media thickness among Korean midlife women

ObjectivesTo evaluate the association between vasomotor symptoms (VMS) and carotid intima-media thickness (CIMT) in Korean midlife women. Study designThis cross-sectional study included 918 Korean women aged 45–65 years who attended their routine health checkup at a single institution between 2013 and 2016. Main outcome measuresAll participants’ results on the Menopause Rating Scale were used to assess the VMS. Severe and very severe VMS were combined into severe VMS. CIMT and blood flow velocities were measured on the common carotid arteries using duplex ultrasound. ResultsAll participants’ mean age was 54.73 ± 5.37 years, and 627 (68.3%) were postmenopausal. A total of 401 (43.7%) women reported VMS: 217 (23.6%), mild; 109 (11.9%), moderate; and 75 (8.2%), severe. The mean CIMT was 0.062 ± 0.017 mm and 0.064 ± 0.019 mm in premenopausal and menopausal women, respectively. In the multivariate linear regression analysis, the CIMT of women with moderate VMS was 0.102 mm (95% confidence interval [CI] = 0.002–0.009) more than that of women with no VMA, and the CIMT of women with severe VMS was 0.246 mm (95% CI = 0.012–0.021) more than that of women with no VMS, after adjusting for several confounders, including age, body mass index, and lifestyle factors. Severe VMS were associated with the risk of thickened CIMT (≥0.075 mm) and/or plaques (odds ratio = 2.90, 95% CI = 1.74–4.84) in the logistic regression analysis after adjusting for the same variables. ConclusionsModerate and severe VMS are independently associated with increased CIMT in otherwise healthy Korean midlife women. Clinicians managing midlife women with bothersome VMS should consider screening for subclinical cardiovascular diseases.

Physical activity and vasomotor symptoms in perimenopausal women at Wukirsari Village, Yogyakarta, Indonesia

Background: Menopause is an event that marks the end of the reproductive phase of a woman. Vasomotor symptoms are one of the primary symptoms of menopausal women and affect about 40-60% of perimenopausal women. This research aims to investigate the relationship of physical activity with vasomotor symptoms in perimenopausal women.Methods: The population in this study were 173 women aged 45-54 years who are still experiencing menstruation in the Wukirsari village working area of Puskesmas Cangkringan Sleman-Yogyakarta. The instrument for measuring vasomotor symptoms adopted two questions from the menopause rating scale (hot flushes and night sweats) questionnaire while measuring physical activity using a questionnaire from Riskesdas. Data were analyzed using SPSS version 23 for Windows.Results: Most of the participants were in the 45-50 years age group (75.73%), followed by severe vasomotor symptoms (95.95%), sufficient physical activity (91.91%), medium level education (49.71%), and informal occupation (94.80%). In addition, this study found that most of the participants were normal Body Mass Index (BMI) (54.34%), passive smoking (64.74%), and pre-hypertension (46.20%). There was a significant relationship between physical activities and BMI to the vasomotor symptoms among women of perimenopausal age (p<0.05).Conclusion: There was a significant relationship between physical activities and BMI the vasomotor symptoms among women of perimenopausal age.

Novel oral combined 17β-estradiol (E2) and micronized progesterone (P4) therapy improves vasomotor symptoms (VMS) and sleep in postmenopausal women (PW)

Introduction: Sleep disruption/chronic insomnia occurs in over 50% of PW, has a negative impact on quality of life (QOL), and is correlated with severity of VMS. While oestrogen improves sleep by direct/indirect mechanisms, P4 taken orally undergoes hepatic first pass effect, producing metabolites with a sedative action and the potential to improve sleep quality.

Hormonal Replacement Therapy in Surgically Induced Menopause: A Prospective Cross Section Study from a Tertiary Care Institution from A Sub-himalayan State

Background: Early surgical menopause increases risk of cardiovascular disease, osteoporosis, fracture, cognitive impairment and sexual dysfunction than women with late menopause. Estrogen therapy (ET) remains the most effective therapy for vasomotor symptoms related to surgically induced menopause. Meterials and Methods: It was a prospective cross-section study. Result: Amongst 255 symptomatic women, 163 (63.92%) women had severe vasomotor symptoms and 54 (33.12% of 163 women) of them had very incapacitating symptoms with marked reduction in their quality of life. 59 (23.13%) women had moderate symptoms with mild disturbances in their sleep while 33 (12.94%) women had only mild symptoms. Conclusion: It is agreed that women who undergo bilateral oophorectomy before the onset of natural menopause should be considered for estrogen therapy for the management of vasomotor symptoms until the average age of natural menopause.

Effects of resistance training on quality of life in postmenopausal women with vasomotor symptoms

Objective Most women experience vasomotor symptoms (VMS) around menopause that may affect quality of life negatively. Effective pharmacological treatment exists but is not recommended for all women, and there is a demand for alternatives to reduce symptoms and improve quality of life. The objective of this study was to investigate the effect of a resistance training intervention on health-related quality of life (HRQoL) in postmenopausal women with VMS. Methods This open randomized controlled trial included 65 postmenopausal women >45 years old with daily VMS. The participants were randomized to 15 weeks of resistance training three times per week or an untreated control group. The Women’s Health Questionnaire (WHQ) and Short Form Health Survey (SF-36) were used to assess HRQoL at baseline and after 15 weeks. Results The resistance training group improved compared to the control group in the WHQ domains of VMS (p = 0.002), sleep problems (p = 0.003) and menstrual symptoms (p = 0.01) from baseline to post intervention. No significant between-group differences were found in SF-36 summary scores, or in any of the domains. Conclusion In postmenopausal women with moderate to severe VMS, resistance training three times per week for 15 weeks improved menopause-specific HRQoL.

What happens after menopause? (WHAM): A prospective controlled study of sleep quality up to 12 months after premenopausal risk-reducing salpingo-oophorectomy

ObjectiveSleep difficulties impair function and increase the risk of depression at menopause and premenopausal oophorectomy may further worsen sleep. However, prospective data are limited, and it remains uncertain whether Hormone Therapy (HT) improves sleep. This prospective observational study measured sleep quality before and up to 12 months after risk-reducing salpingo-oophorectomy (RRSO) compared to a similar age comparison group who retained their ovaries. MethodsNinety-five premenopausal women undergoing RRSO and 99 comparisons were evaluated over a 12-month period using the Pittsburgh Sleep Quality Index (PSQI). ResultsAlmost half reported poor sleep quality at baseline. Overall sleep quality was not affected by RRSO until 12 months (p = 0.007). However, sleep disturbance increased by 3 months and remained significantly elevated at 12 months (p < 0.001). Trajectory analysis demonstrated that 41% had increased sleep disturbance after RRSO which persisted in 17.9%. Risk factors for sleep disturbance included severe vasomotor symptoms, obesity and smoking. Around 60% initiated HT after RRSO. Sleep quality was significantly better in HT users vs non users (p = 0.020) but HT did not restore sleep quality to baseline levels. ConclusionsOverall sleep quality is not affected by RRSO, but new onset sleep disturbance is common, particularly in those with severe vasomotor symptoms. Clinicians should be alert to new-onset sleep disturbance and the potential for HT to improve sleep quality.

Effects of neurokinin 3 receptor antagonist fezolinetant on hot flash-like symptoms in ovariectomized rats

The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of fezolinetant (1–10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of fezolinetant for the treatment of VMS associated with menopause.

Modeling shows the NK3R antagonist, ACER-801, reduces treatment-induced vasomotor symptoms.

e13013 Background: Hot flashes or vasomotor symptoms (VMS) are a common side effect of hormone deprivation (HD) therapy. Up to 80 % of cancer patients treated with tamoxifen (antiestrogen treatment) or leuprolide (androgen deprivation) have VMS. In some cases, patients discontinue HD therapy due to VMS severity and lower quality of life; therefore, reducing VMS is critical for patient compliance. NK3 receptor (NK3R) antagonists have previously been shown to reduce VMS in postmenopausal women. ACER-801 is a candidate NK3R antagonist drug intended to alleviate VMS severity when used with HD therapy. We used Quantitative Systems Pharmacology (QSP) modeling to predict the likely efficacy of ACER-801 in patients on HD therapy and evaluate the potential of hepatic drug-drug interactions between ACER-801 and tamoxifen or leuprolide. Methods: The model is composed of KNDy neurons in the arcuate nucleus with NKB, dynorphin, and estradiol effects on KNDy neurons, HPG axis, sex hormones, and neuroendocrine feedback. ACER-801, tamoxifen, and leuprolide PK, PD, and hepatic metabolism are included in the model. The model was developed, qualified, and tested using literature data. A tamoxifen-treated postmenopausal female virtual patient (VP) and leuprolide-treated male VP were created based on typical patients included in clinical trials. VMS severity and frequency were estimated based on the level of NKB binding to NK3R. Results: In the male VP, simulated leuprolide administration induced hypertrophy of KNDy neurons and VMS over six months. Coadministration of ACER-801 with leuprolide reduced VMS frequency and severity to near 0 in short-term (5-week) simulations. Simulations predict ACER-801 will not alter leuprolide metabolism nor increase plasma testosterone concentrations. Tamoxifen treatment increased VMS by 15% in simulations with the postmenopausal VP. Coadministration of ACER-801 with tamoxifen in this VP reduced VMS by 75% compared to tamoxifen monotherapy. ACER-801 had minimal effects on plasma estradiol concentrations in the postmenopausal VP. Drug-drug interactions between ACER-801 and tamoxifen were dependent on the simulated bioavailability of ACER-801. Using current estimates of ACER-801 bioavailability in the model, the hepatic concentration of ACER-801 had limited effects on tamoxifen metabolism, which are not expected to necessitate dose adjustments. Conclusions: Using a QSP neurobiology model as a research tool enabled us to evaluate the efficacy of the NK3R antagonist, ACER-801, to treat HD therapy-induced VMS. Simulations show ACER-801 may be highly efficacious for the treatment of induced-VMS. The research provided estimates of DDI with ACER-801 and tamoxifen and what clinical experiments would be needed to confirm those estimates.

Association of single nucleotide polymorphisms of cytochrome P450 enzymes with experience of vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients: a systematic review

BackgroundAdjuvant endocrine therapies are known to induce undesirable adverse effects such as vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients. Drugs used in these therapies are often metabolised by cytochrome P450 (CYP) enzymes, in which their metabolising activities can be modified by single nucleotide polymorphisms (SNP) in CYP genes and CYP genotypes. This review aims to explore whether SNPs or genotypes of CYP are associated with the occurrence, frequency and severity of vasomotor, vaginal and musculoskeletal symptoms in breast cancer patients on adjuvant endocrine therapies.MethodsA literature review was conducted using five electronic databases, resulting in the inclusion of 14 eligible studies, and their findings were presented narratively. Selected items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist were used for critical appraisal of the reporting quality of the included studies.ResultsMost of the included studies showed that SNPs or genotypes of CYP that modify its metabolising activity have no effect on the occurrence, frequency or severity of vasomotor symptoms, including hot flashes. One study showed no correlation of these genetic variations in CYP with musculoskeletal symptoms, and no data were available on the association between such genetic variations and vaginal symptoms.ConclusionsOverall, genetic variations in CYP have no effect on the experience of hot flashes among breast cancer patients. We recommend exploration of the link between the active metabolites of chemotherapeutic drugs and the molecules shown to affect the occurrence or severity of hot flashes, and the establishment of the relationship between such genetic variations and patients’ experience of musculoskeletal and vaginal symptoms. Subgroup analyses based on patients’ duration of adjuvant endocrine therapies in such studies are recommended.

A core outcome set for vasomotor symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative.

Vasomotor symptoms (VMS) (hot flashes and night sweats) affect most women over the menopause transition. Comparing the safety and effectiveness of treatments for vasomotor symptoms is limited by the use of inconsistent outcome measures, and uncertainty as to which outcomes are most important to symptomatic women. To address this, we have developed a Core Outcome Set (COS) for use in clinical trials of treatments for VMS. We systematically reviewed the primary outcomes measured in randomized controlled trials of treatments for VMS. These were refined and entered into a two-round modified Delphi survey completed by clinicians, researchers, and postmenopausal women between November 2019 and March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." Two international consensus meetings were held to finalize the COS. Based on the systematic review, 13 separate outcomes were included in the Delphi process. This was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to categorize importance scores obtained during Round 2 of the Delphi survey. These informed discussions at the consensus meetings which were attended by 56 participants from 28 countries. The final COS includes six outcomes: 1) frequency of VMS, 2) severity of VMS, 3) distress, bother or interference caused by VMS, 4) impact on sleep, 5) satisfaction with treatment, and 6) side-effects of treatment. Implementation of this COS will: better enable research studies to accurately reflect the joint priorities of postmenopausal women, clinicians and researchers, standardize outcome reporting, and facilitate combining and comparing results from different studies, and ultimately improve outcomes for women with bothersome VMS.

Qualitative study: burden of menopause-associated vasomotor symptoms (VMS) and validation of PROMIS Sleep Disturbance and Sleep-Related Impairment measures for assessment of VMS impact on sleep

PurposeWe evaluated the impact of menopause-associated vasomotor symptoms (VMS) on sleep. We also sought to establish the content validity of Patient-Reported Outcomes Measurement Information System (PROMIS) short form Sleep-Related Impairment and Sleep Disturbance measures in postmenopausal women with moderate to severe VMS.MethodsCross-sectional, in-person, qualitative interviews were conducted in the United States (Texas, Illinois) and European Union (UK, France) with women aged 40–64 years experiencing moderate to severe VMS (≥35/wk). Main outcomes were impact of VMS on sleep based on concept elicitation and content validity of PROMIS Sleep-Related Impairment and Sleep Disturbance short forms via cognitive debriefing.ResultsThirty-two women (US: n = 16; EU: n = 16) participated. A majority (US: 93.8%; EU: 93.8%) said VMS affected sleep; specifically, they had sleep interrupted by sweating or overheating and had difficulty returning to sleep. Sleep disturbance was the most bothersome aspect of VMS (US: 75%; EU: 50%). VMS-associated sleep disturbance affected next-day work productivity, mood, relationships, daily activities, concentration, social activities, and physical health. Participants found both PROMIS sleep measures relevant and easy to answer; the Sleep Disturbance measure was considered the most relevant. Participants had no difficulty remembering their experiences over the 7-day recall period and found the response options to be distinct.ConclusionVMS associated with menopause significantly interferes with sleep and next-day functioning (e.g., work productivity), supporting assessment of sleep outcomes in studies evaluating treatment of VMS. Women with moderate to severe VMS found that the PROMIS Sleep-Related Impairment and Sleep Disturbance short forms assessed constructs important to understanding sleep in the context of menopause-associated VMS.

Abstract PS8-41: Low dose tamoxifen for breast cancer prevention and mammographic density reduction - a randomized controlled trial

Abstract Introduction: Tamoxifen prevents breast cancer in high-risk women and reduces recurrence in the adjuvant setting but comes with side-effects. The optimal dose to increase uptake and retain therapeutic effect is unknown. We tested if the efficacy of low-dose tamoxifen is non-inferior to standard dose using mammographic density as a proxy for therapy response and if lower doses are associated with fewer symptoms.Methods: Healthy pre- and postmenopausal women attending a mammography screening program aged 40 to 74 years were invited to participate. N=2,314 screening women were investigated for eligibility. Exclusion criteria were women with a low mammographic density (BI-RADS A), high blood pressure, pregnancy, use of hormonal therapy, previous cardiovascular disorder, uncontrolled diabetes, any previous cancer. N=1,440 women entered a six-months double-blind placebo-controlled randomized dose-determination trial that was conducted in 2016-2019. Women were allocated into six months oral daily administration of 1, 2.5, 5, 10, and 20 mg of tamoxifen or placebo.Mammographic density was assessed as radiographic dense fibro-glandular tissue using a fully automated density tool. Symptoms were assessed using a self-reported questionnaire including vasomotor, gynecological, sexual, and joint pain symptoms. Non-inferior reduction of mammographic density and fewer severe symptoms in lower doses were compared with standard dose 20 mg. Post-hoc analyses were performed by menopause status. Both per protocol and intension to treat populations were analyzed.Results: Premenopausal (N=566) and postmenopausal (N=873) participants were recruited to the study. Premenopausal women showed non-inferior reduction in mammographic density following 2.5, 5 and 10 mg tamoxifen compared with the median 9.7% decrease observed in the 20 mg group (Table 1). No reduction in density was seen in postmenopausal participants. Severe vasomotor symptoms (hot flashes, cold and night seats) were reduced by approximately 50% in the 2.5 mg group compared with the 20 mg group (Table 2).Conclusion: Premenopausal women experienced fewer side effects with non-inferior decrease in breast density at lower dose of tamoxifen (2.5 mg) compared with standard dose (20 mg). A low dose of tamoxifen could be used for prevention and to increase sensitivity of a mammogram in premenopausal women. The table shows the proportions of women that had a larger decrease than median density decreases in the 20 mg arm (-9.7%) at six-months, stratified by menopausal status and tamoxifen dose. The table shows the prevalence ratios (PR) of severe vasomotor symptoms stratified by menopausal status and tamoxifen dose. Table 1. Non-inferior dense area reduction at six-months in the 2.5 mg arm compared with the standard dose 20mg arm.All womenPremenopausalPostmenopausalDoseProportion (97.5%CI)p-valueHolm p-valueProportion (95%CI)Proportion (95%CI)0 mg41.0 (29.2,100)0.1010.20333.9 (15.0,52.8)44.6 (33.3,55.9)1 mg40.8 (28.1,100)0.1250.20333.3 (17.9,48.8)46.1 (31.9,60.3)2.5 mg55.3 (44.2,100)&amp;lt;0.01&amp;lt;0.0171.9 (57.7,86.0)44.2 (31.2,57.2)5 mg54.8 (44.8,100)&amp;lt;0.01&amp;lt;0.0177.3 (64.4,90.1)38.5 (26.8,50.1)10 mg54.5 (42.9,100)&amp;lt;0.01&amp;lt;0.0172.7 (59.6,85.8)42.6 (28.9,56.3)20 mg50.0 (ref.)63.841.2 Table 2. Significantly lower prevalence ratios of severe vasomotor symptoms by 50% at six-months in the 2.5 mg arm compared with the standard dose 20 mg arm.All womenPremenopausalPostmenopausalDosePR (95%CI)PR (95%CI)PR (95%CI)0 mg0.41 (0.27,0.62)0.10 (0.02,0.39)0.56 (0.36,0.88)1 mg0.48 (0.33,0.71)0.37 (0.19,0.75)0.56 (0.35,0.89)2.5 mg0.47 (0.32,0.71)0.37 (0.18,0.78)0.54 (0.33,0.88)5 mg0.72 (0.51,1.01)0.36 (0.18,0.75)0.97 (0.65,1.42)10 mg0.76 (0.55,1.06)0.68 (0.39,1.19)0.81 (0.54,1.22)20 mg1 (ref.)1 (ref.)1 (ref.) Citation Format: Per Hall, Mikael Eriksson, Kamila Czene. Low dose tamoxifen for breast cancer prevention and mammographic density reduction - a randomized controlled trial [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 PS8-41.

Who is managing menopausal symptoms, sexual problems, mood and sleep disturbance after breast cancer and is it working? Findings from a large community-based survey of breast cancer survivors.

To determine the nature and severity of vasomotor symptoms, sexual problems, mood and sleep disturbance in community-dwelling breast cancer patients, whether and where they received treatment for these symptoms and their satisfaction with treatment received. Online cross-sectional survey distributed through Breast Cancer Network Australia (BCNA). 524/2286 women responded to the invitation to participate. Of these, 74% (385/523) reported symptoms of interest and were included in the analysis. Mean age was 55.2years and mean time since breast cancer diagnosis was 5.7years. Most (66%) had received chemotherapy and were taking endocrine therapy (64%). The most common symptoms were hot flushes/night sweats and sleep disturbance (both 89%), vaginal dryness (75%), mood swings (62%) and sexual problems (60%). Symptoms were mild (21-33%) or moderate (21-38%) in around one third and severe in up to one quarter (8-26%). Symptoms affected the ability to "get on with their life" for 36%, predicted by severity of hot flushes (OR 1.4), sleep disturbance (OR 1.3), mood disturbance (OR 1.3), and sexual problems (OR 1.3). Only 32% were offered treatment, mostly delivered by GPs (33%) or oncologists (26%). Only 49% found this "somewhat effective" and 34% found it ineffective. The majority (60%) wanted more support to manage their symptoms. Menopausal symptoms, sexual problems, mood and sleep difficulties are common after breast cancer and often not effectively managed. There is an unmet need for coordinated care providing effective treatments.

Effects of combined 17β-estradiol and progesterone on weight and blood pressure in postmenopausal women of the REPLENISH trial

Objective:To examine the impact of a single-capsule 17β-estradiol (E2)/progesterone (P4) on weight and blood pressure (BP) when treating moderate to severe vasomotor symptoms in postmenopausal women with a uterus.Methods:Healthy postmenopausal women with a uterus (aged 40-65, body mass index ≤34 kg/m2, BP ≤140/90 mm Hg) were randomized to daily E2/P4 (mg/mg; 1/100, 0.5/100, 0.5/50, 0.25/50) or placebo in the phase 3 REPLENISH trial (NCT01942668). Changes in weight and BP from baseline to month 12 were evaluated. Potentially clinically important changes were defined as increases or decreases from baseline in weight by ≥15% and ≥11.3 kg, systolic BP by ≥20 mm Hg (absolute value ≥160 or ≤90 mm Hg), and diastolic BP by ≥15 mm Hg (absolute value ≥90 or ≤60 mm Hg).Results:Overall mean changes in weight and BP from baseline to month 12 with E2/P4 were modest and generally not statistically or clinically significant versus placebo. Incidence of potentially clinically important changes was low for weight (E2/P4 vs placebo: 1.1-2.6% vs 2.2%), systolic BP (0.3-1.1% vs 1.1%), and diastolic BP (1.4-4.2% vs 3.2%). A small number of women had treatment-related, treatment-emergent adverse events of weight gain (1.4-2.6% vs 1.3%) or hypertension (0.2-1.2% vs 0%). Few women who discontinued E2/P4 had weight gain (1.6%) or hypertension (0.6%) as a primary reason. Efficacy profile on VMS was consistent with previous findings and not modified by body mass index.Conclusions:Twelve-month use of E2/P4 had no clinically meaningful impact on weight or BP in postmenopausal women of the REPLENISH study.