Women's Health Initiative Trial Research Articles

The 2017 Women’s Health Initiative study and use of hormone therapy: an emulated repeated cross-sectional study

BackgroundHormone therapy (HT) use among menopausal women declined after negative information from the 2002 Women’s Health Initiative (WHI) HT study. The 2017 post-intervention follow-up WHI study revealed that HT did not increase long-term mortality. However, studies on the effects of the updated WHI findings are lacking. Thus, we assessed the impact of the 2017 WHI findings on HT use in Taiwan.MethodsWe identified 1,869,050 women aged 50–60 years, between June and December 2017, from health insurance claims data to compare HT use in the 3 months preceding and following September 2017. To address the limitations associated with interval-censored data, we employed an emulated repeated cross-sectional design. Using logistic regression analysis, we evaluated the impact of the 2017 WHI study on menopausal symptom-related outpatient visits and HT use. In a scenario analysis, we examined the impact of the 2002 trial on HT use to validate our study design.ResultsStudy participants’ baseline characteristics before and after the 2017 WHI study were not significantly different. Logistic regressions demonstrated that the 2017 study had no significant effect on outpatient visits for menopause-related symptoms or HT use among women with outpatient visits. The scenario analysis confirmed the negative impact of the 2002 WHI trial on HT use.ConclusionsThe 2017 WHI study did not demonstrate any impact on either menopause-related outpatient visits or HT use among middle-aged women in Taiwan. Our emulated cross-sectional study design may be employed in similar population-based policy intervention studies using interval-censored data.

Abstract PS07-03: Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis

Abstract Background Findings from cohort studies compared with those from the Women's Health initiative (WHI) randomized, placebo-controlled clinical trial regarding estrogen-alone and breast cancer risk are discordant. The WHI randomized trial enrolled 10,729 postmenopausal women with prior hysterectomy, mean age 64 years (33.2% 50-59), no prior breast cancer and a non-suspicious baseline mammogram. After 7.2 years intervention and 16.2 years cumulative follow-up, conjugated equine estrogen (CEE)-alone (vs placebo) significantly reduced breast cancer incidence by 22% (P = 0.005) and significantly reduced breast cancer mortality by 40% (P = 0.04) (Chlebowski JAMA 2020). In contrast, cohort studies had opposite findings, estrogen-alone use was associated with significantly higher breast cancer incidence and significantly higher breast cancer mortality. Therefore, we identified all available estrogen-alone randomized clinical trials where breast cancer findings were reported to conduct a meta-analysis examining the totality of the randomized clinical trial evidence regarding estrogen-alone influence on breast cancer incidence. Methods We conducted PubMed and Google Scholar searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analyses and reviews. In the current meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, a different method was used, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. Findings Ten randomized trials, incorporating WHI findings, and findings from nine smaller trials included 14,272 randomized participants and 591 incident breast cancers. Of 9 smaller trials, 6 required negative baseline screening mammograms; mean entry age: 50 to 56 years in 5 trials and 62 to 71 years in 4 trials. In the nine smaller trials, 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) were diagnosed with breast cancer, respectively (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. In the WHI trial, 4.5% (238 of 5310) vs 5.5% (296 of 5429) randomized to estrogen-alone were diagnosed with breast cancer, respectively (RR 0.78 95% CI 0.65-0.93, P = 0.005)). Combining smaller trials and WHI results, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo were diagnosed with breast cancer, respectively (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). Results from a sensitivity analysis for the smaller trials using exact conditional logistic regression were essentially unchanged (RR 0.64 95% CI 0.35-1.13). Interpretation The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use, among postmenopausal women with prior hysterectomy, significantly reduces breast cancer incidence. This consistent pattern seen in these randomized trials suggests the WHI CEE-alone findings are not “stand alone” outcomes or due to chance. Citation Format: Rowan Chlebowski, Aaron Aragaki, Kathay Pan, Joanne Mortimer, Karen Johnson, Jean Wactawski-Wende, Meryl LeBoff, Sayeh Lavasani, Dorothy Lane, Rebecca Nelson, JoAnn Manson. Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-03.

Risk of Adverse Cardiovascular Outcomes in Postmenopausal Women with Inflammatory Bowel Disease.

Individuals with inflammatory bowel disease (IBD) who lack traditional cardiovascular disease (CVD) risk factors, such as young females, are observed to experience adverse CVD outcomes. Whether women with IBD have increased CVD risk after the menopause transition is unclear. We conducted a survival analysis of Women's Health Initiative (WHI) participants and excluded those with missing IBD diagnosis, model covariate data, follow-up data, or a baseline history of the following CVD outcomes: coronary heart disease (CHD), ischemic stroke, venous thromboembolism (VTE), peripheral arterial disease (PAD). Risk of outcomes between IBD and non-IBD women was performed using Cox proportional hazard models, stratified by WHI trial and follow-up. Models were adjusted for age, socio-demographics, comorbidities (e.g., hypertension, diabetes, hypercholesterolemia, etc.), family history, and lifestyle factors (e.g., smoking, alcohol, physical activity, body mass index, etc.). Of 134,022 WHI participants meeting inclusion criteria, 1367 (1.0%) reported IBD at baseline. Mean baseline age was 63.4 years. After adjusting for age and other confounders, no significant difference was observed between IBD and non-IBD women for the risk of CHD (HR 0.96, 95% CI 0.73-1.24), VTE (HR 1.11, 95% CI 0.81-1.52) or PAD (HR 0.64, 95% CI 0.28-1.42). After adjusting for age, risk of ischemic stroke was significantly higher (HR 1.41, 95% CI 1.06-1.88) in IBD than non-IBD women. With further adjustment, the excess risk of ischemic stroke among IBD women was attenuated and no longer statistically significant (HR 1.31, 95% CI 0.98-1.76). Among postmenopausal women with IBD, risk of ischemic stroke may be higher than in non-IBD women.

Part I: Interactive case: Menopause

Part I: Interactive case: Menopause

The Menopause Management Vacuum.

The burden of untreated menopause symptoms in midlife women is substantial and can result in reduced quality of life as well as lost work productivity, lost opportunities for advancement at work, and increased health care costs. Unfortunately, the health care system is largely unprepared to help women manage these symptoms, which have a mean duration of 7 to 9 years. Hormone therapy usage rates have plummeted following publication of the results of the Women's Health Initiative trials due to safety concerns. In addition, postgraduate medical training programs include minimal to no training on menopause management. These and other factors have contributed to what is essentially a menopause management vacuum. This vacuum created a market opportunity, particularly given the fact that midlife women are potent drivers of the global economy. In this review, we outline the menopause management gaps and discuss a multipronged approach to close these gaps and improve the care of midlife women.

DREAM, a possible answer to the estrogen paradox of the Women's Health Initiative Trial

Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women's Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30core) and post-treatment (PRESTO-45surg) gene expression profiles. The PRESTO-30core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45surg, thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show estrogen modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Abstract 4374: CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up studies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, was to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland. Pathway analysis from RNA-sequencing revealed Aryl Hydrocarbon Receptor (AHR) signaling as the top canonical pathway affected by treatment with CE+BZA. Previous studies reported that 4-hydroxytamoxifen, a metabolite of the SERM tamoxifen, was able to activate the AHR pathway. In our study we determined that BZA treatment activated the AHR pathway in both ERα-positive and ERα-negative cell lines. BZA increased expression of aryl hydrocarbon receptor repressor (AHRR) in cell lines and increased expression of two AHR pathway members, CYP1A1 and CYP1B1, in tumors of estrogen-sensitive polyoma middle T antigen (PyMT) mice. AHRR has been reported to act as a tumor suppressor in breast cancer; therefore activation of AHR by BZA in women taking CE+BZA combination therapy might be one mechanism by which outgrowth of occult tumors is decreased. Further evaluation of the role of AHR in breast cancer is necessary to improve our understanding of CE+BZA action. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4374.

The Women's Health Initiative Estrogen-alone Trial had differential disease and medical expenditure consequences across age groups.

The Women's Health Initiative (WHI) randomized trial identified age differences in the benefit-risk profile of estrogen-alone (ET) use. The impact of WHI trial on disease-associated medical expenditures attributable to subsequent decreased ET utilization has, however, not been measured. Therefore, the objective of this analysis was to quantify the age-specific disease-associated medical expenditures attributable to reduced ET utilization after the WHI Hormone Therapy (HT) trials. Population-level disease counts and associated expenditures between 2003 and 2015 were compared between an observed ET-user population versus a hypothetical ET-user population assuming absence of the WHI HT trials, constructed by extrapolating ET utilization rates from 1996 to 2002 assuming pre-WHI HT rates would have continued without publication of the WHI HT trial data (2002-2004). Analyses were stratified by age (50-59, 60-69, and 70-79 years). Input data were extracted from Medical Expenditure Panel Survey and the literature. The primary outcomes were: ET utilization, chronic diseases (breast cancer, stroke, coronary heart disease, colorectal cancer, pulmonary embolism, and hip fracture) and disease-associated direct medical expenditures. Over 13 years, the decline in ET utilization was associated with $4.1 billion expenditure for excess chronic diseases (37,549 excess events) among women in their 50s, compared to savings of $1.5 billion and $4.4 billion for diseases averted by lower ET utilization among women in their 60s (13,495 fewer events) and 70s (40,792 fewer events), respectively. The decline in ET utilization had differential disease and expenditure consequences by age groups in the United States. These results are limited by the lack of inclusion of vasomotor symptom benefit and costs of alternative medications for these symptoms in the analysis.

The Women's Health Initiative trials of menopausal hormone therapy: lessons learned.

The Women's Health Initiative (WHI) assessed oral conjugated equine estrogens (CEE) taken with or without medroxyprogesterone acetate (MPA) for prevention of chronic disease in postmenopausal women aged 50-79 years. Women with an intact uterus (n = 16,608) were randomized to CEE+ MPA therapy or placebo for a median of 5.6 years; women with hysterectomy (n = 10,739) were randomized to CEE-alone therapy or placebo for a median of 7.2 years. Both cohorts have been followed for 18 years. In the overall study population (mean age, 63 y), neither estrogen-progestin therapy (EPT) nor estrogen-only therapy prevented coronary heart disease or led to a favorable balance of chronic-disease benefits and risks. Subgroup analyses, however, suggest that timing of hormone therapy (HT) initiation influences the relation between HT and coronary risk, as well as its overall benefit-risk balance, with more favorable effects in women who are younger (age < 60 year) or recently menopausal (within 10 year) than in women who are older or further past the menopausal transition. In younger women who entered the trial of estrogen-only therapy with oophorectomy, the intervention was associated with a significant 32% reduction in all-cause mortality over long-term follow-up. WHI findings indicate important differences in HT-related clinical outcomes by age and time since menopause. Systemic HT has an acceptable safety profile for menopause management when initiated among healthy women who are younger (or recently menopausal) and not at elevated risk for cardiovascular disease or breast cancer. Initiation of treatment in older women who are distant from menopause onset, however, should be avoided. Other HT formulations and routes of delivery warrant further study.(WHI clinicaltrials.gov identifier: NCT00000611).

Low-fat dietary pattern and global cognitive function: Exploratory analyses of the Women's Health Initiative (WHI) randomized Dietary Modification trial

BackgroundMeta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function. MethodsThe Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini–Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611. FindingsAmong the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38–0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35–1.19) and HR of 0.63 (95% CI 0.19–2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16). InterpretationAdoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women. FundingSeveral Institutes of the US National Institutes of Health.

The Controversial History of Hormone Replacement Therapy.

The history of hormone replacement therapy (HRT) started in the 1960s, with very high popularity in the 1990s. The first clinical trials on HRT and chronic postmenopausal conditions were started in the USA in the late 1990s. After the announcement of the first results of the Women’s Health Initiative (WHI) in 2002, which showed that HRT had more detrimental than beneficial effects, HRT use dropped. The negative results of the study received wide publicity, creating panic among some users and new guidance for doctors on prescribing HRT. The clear message from the media was that HRT had more risks than benefits for all women. In the following years, a reanalysis of the WHI trial was performed, and new studies showed that the use of HRT in younger women or in early postmenopausal women had a beneficial effect on the cardiovascular system, reducing coronary disease and all-cause mortality. Notwithstanding this, the public opinion on HRT has not changed yet, leading to important negative consequences for women’s health and quality of life.

Best practices in care for menopausal patients: 16 years after the Women's Health Initiative.

The Women's Health Initiative (WHI) was a large, randomized clinical trial funded by the National Institutes of Health to determine whether menopause hormone therapy (MHT) prevented heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. Two WHI trials were stopped early, and the findings had a profound effect on the clinical practice guidelines related to postmenopausal health. This article provides an overview of the WHI MHT clinical trials and findings, discusses the early stoppage of the trials and subsequent implications, and details the current nomenclature and treatment options for women transitioning through menopause in light of the WHI. This study is based on a comprehensive literature review and an education activity developed by the American Association of Nurse Practitioners. To best serve patients and individualize therapy, clinicians must provide the best estimate of potential risks or benefits to the individual patient. It is important to balance evidence of symptom relief with long-term risks and benefits that fit the patient's characteristics of family and personal health history. Armed with evidence to support various hormonal and non-hormonal options, well-informed clinicians can counsel women about MHT and potentially avoid negative impact on quality of life.

Abstract LB-170: Breast cancer incidence and hormone therapy use before and after the Women’s Health Initiative (WHI) estrogen (E) plus progestin (P) trial by race/ethnicity

Abstract We examined breast cancer incidence in US women, 50 years or older, from the Surveillance, Epidemiology and End Results (SEER) program through 2015 in relation to estrogen (E) plus progestin (P) and E alone use before and after 2002, when adverse E plus P breast cancer effects in the WHI trial were initially reported. Age-adjusted annual breast cancer incidence rates for all US women averaged over the five-year intervals of 1983-1987, 1988-1992, 1993-1997, 1998-2002, 2003-2007, 2008-2012, 2013-2015 (3 year interval) were 330, 358, 368, 387, 345, 352 and 357 breast cancers per 100,000 women. After early quinquennial-to-quinquennial interval increases in breast cancer incidence, the surprising and sustained reduction in breast cancer incidence rates seen beginning in 2003 (Ravdin et al NEJM 2007) has been largely attributed to the substantial (70%) reduction in E plus P use over the same period (Jewett et al Obstet Gynecol 2014). However, differences in breast cancer incidence trends by race/ethnicity have emerged. Over the same quinquennial intervals, among White women, there were 343, 374, 383, 407, 359, 362 and 367 breast cancers per 100,000 women, following the same pattern of increases followed by sustained decrease beginning in 2003. In contrast, Black women experienced no substantial reduction in breast cancer incidence after 2003 with subsequent sustained increases through 2015 with quinquennial intervals rates of 277, 302, 327, 329, 328, 350, 356 breast cancers per 100,000 women with most recent incidence rates now comparable to White women. Based on reported findings of the WHI hormone therapy clinical trials and the sustained reduction seen in the US for both E plus P and E alone use (the latter for women with prior hysterectomy), we propose a hypothesis that the discordant trends in breast cancer incidence between White and Black women can largely be explained by the sustained changes in hormone therapy use beginning in 2003. In the WHI randomized trials, E plus P and E alone had opposite effects on breast cancer risk, E plus P initiation increasing breast cancer risk, further increasing with duration, with increased risk sustained for over a decade following cessation, and E alone decreasing risk at initiation and cessation (Chlebowski et al JAMA Oncology 2015). In 2003, E plus P use was higher in White compared to Black women. Thus, the reduction in E plus P use, cessation and decreased imitation, in White women was associated with prolonged reduction in breast cancer incidence. In contrast, with hysterectomy more common in Black women, decisions not to initiate E alone use could have increased their breast cancer risk. Thus, consideration of differential use of these two hormone regimens in Black and White women provides a plausible explanation for differential changes in breast cancer incidence seen in these two populations over recent quinquennial periods. Citation Format: Rowan T. Chlebowski, Aaron K. Aragaki, Garnet L. Anderson, Ross L. Prentice. Breast cancer incidence and hormone therapy use before and after the Women’s Health Initiative (WHI) estrogen (E) plus progestin (P) trial by race/ethnicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-170.

Abstract P6-13-04: Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials

Abstract OBJECTIVE: To quantitate breast cancer incidence (BrCa-I) and mortality (BrCa-M) outcome differences between the two Women's Health Initiative (WHI) HRT trials,1,2 the ratio of hazards was calculated for estrogen-alone based hormone replacement therapy (E-HRT) vs. placebo (P), and E + progestin Provera (ProgProv) combination HRT vs. P trials. METHODS: Hazard ratios (HR) of BrCa-I and BrCa-M and 95% confidence intervals (CI) were obtained from both WHI HRT trials. Subsequently, to compare BrCa outcomes between E-HRT vs. E + ProgProv, the ratios of HRs between the trials (HR1/HR2) were estimated separately for i. BrCa-I all women, ii. BrCa-I low Gail score (Gail score &amp;lt;1.75*), and iii. BrCa-M. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Outcome Comparison, the two WHI HRT randomized trials. Ratio of Hazards, BrCa Incidence and BrCa mortality E-HRT vs. P, HR1 (95% CI)E-HRT + ProgProv vs. P, HR2 (95% CI)HR1/HR2 (95% CI)pBrCa-I All Woman10.77 (0.62-0.95)1.25 (1.07-1.46)0.62 (0.47-0.80)0.0004BrCa-I Low Gail Score* (Gail score &amp;lt;1.75)10.65 (0.50-0.86)1.24 (1.01-1.51)0.53 (0.38-0.74)0.0002BrCa-M20.55 (0.33-0.92)1.44 (0.97-2.15)0.38 (0.20-0.75)0.004*Gail score &amp;lt;1.75; HRs calculated from Reference 1, Figure 3 CONCLUSIONS: Our calculations show that the different outcomes between the two WHI HRT trials, estimated as ratio of hazards, are highly significant on statistical basis, both for BrCa incidence and for BrCa mortality. These findings highlight the potential carcinogenic impact of ProgProv and the major public health benefits of HRT based on E alone. REFERENCES: 1. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. The Lancet Oncology 2012;13:476-86. 2. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. Citation Format: Ragaz J, Qian H, Wong H, Wilson KS, Shakeraneh S, Spinelli JJ. Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-04.

Vitamin D with calcium supplementation and risk of atrial fibrillation in postmenopausal women

Atrial fibrillation (AF) is the most common arrhythmia in adults. Although vitamin D deficiency is associated with AF risk factors, retrospective studies of association with AF have shown mixed results. We sought to determine the efficacy of calcium and vitamin D (CaD) supplementation for AF prevention in a randomized trial. We performed a secondary analysis of the Women's Health Initiative trial on CaD supplementation versus placebo. We linked participants to their Medicare claims to ascertain incident AF. Among 16,801 included participants, there were 1,453 (8.6%) cases of incident AF over an average of 4.5 years, at an average rate of 19.9 events per 1,000 person-years. We found no significant difference in incident AF rates between the CaD and placebo arms (hazard ratio 1.02 for CaD vs placebo, 95% CI 0.92-1.13). After multivariate adjustment, there was no significant association between baseline 25-hydroxyvitamin D serum levels and incident AF (hazard ratio 0.92 for lowest subgroup vs highest subgroup, 95% CI 0.66-1.28). We present the first analysis of a large randomized trial of daily vitamin D supplementation for AF prevention. We found that CaD had no effect on incidence of AF in Women's Health Initiative CaD trial participants. We also found that baseline serum 25-hydroxyvitamin D level was not predictive of long-term incident AF risk.

The Timing Hypothesis: Hormone Therapy for Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease.

The risks and benefits of menopausal hormonal therapy (HT) have been evaluated extensively over the past three decades. While the efficacy of HT for management of menopausal symptoms, including vasomotor symptoms and vaginal dryness is well established, its relationship to cardiovascular outcomes is complex. The timing hypothesis, which posits that the cardiovascular effects of HT depend on the timing of initiation of HT in relation to menopause, has helped shape our understanding of the cardiovascular outcomes related to HT. Based on results from female monkey studies, the timing hypothesis provides a framework to explain discrepancies in results between multiple observation studies and the Women's Health Initiative (WHI) hormone therapy trials. The WHI trials closed early in 2002 in part because of increased cardiovascular events seen in women on treatment. Subanalysis of the WHI results by age group, and more recent randomized control studies, including the Kronos Early Estrogen and Prevention Study (KEEPS) and Early Versus Late Intervention Trial (ELITE), demonstrate that the risk of adverse cardiovascular events for HT are low for women <60 years of age or within 10 year from menopause. Although current data does not support using HT for primary prevention of cardiovascular disease, it does suggest that HT can be safely used to treat symptoms in appropriately selected women close to menopause.

Abstract 948: Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up sudies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, is to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland, using transcriptome and whole genome occupancy analysis in breast cancer cell lines. RNA-Seq and ChIP-Seq studies suggest that CE+BZA decreases pathways related to S-phase entry, cell cycle regulation and BRCA1. We are also studying the effects of CE+BZA on early mammary cancer progression in the estrogen-sensitive polyoma middle T antigen (PyMT) transgenic mouse model and have observed that treatment with CE+BZA delayed the onset of tumors and decreased their rate of growth. Mice treated with CE+BZA also survived longer. In addition, CE+BZA was able to decrease the rate of tumor growth in an ERα-positive patient-derived xenograft (PDX) mouse model. An improved understanding of the molecular mechanisms of CE+BZA action in hormone sensitive breast cancer cell and animal models should have important implications for women considering HRT. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy [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 948.

Abstract 4237: Estrogen metabolism in menopausal hormone users: Does it differ between estrogen plus progestin and estrogen alone users in the Women’s Health Initiative Observational Study

Abstract Background: The Women’s Health Initiative (WHI) provided divergent results regarding the effects of menopausal hormone therapy (MHT) on breast cancer risk, with women in the conjugated equine estrogen plus medroxyprogesterone (CEE+MPA) arm at elevated risk, and women in the CEE alone arm at reduced risk. Although direct progestin-mediated effects may largely explain the elevated risk, we hypothesize that in addition, these MHT treatments may differentially influence patterns of estrogen metabolism, with CEE alone preferentially inducing metabolism along the 2-hydroxylation pathway, a pattern previously linked to reduced breast cancer risk. Study methods/population: Women in a case-control study of estrogen metabolites (EM) and ovarian and endometrial cancer from the WHI Observational Study were identified for this analysis. Unlike the WHI trial, no medication restrictions were applied. At enrollment, serum, anthropometric measures, and self-administered questionnaires which ascertained reproductive history, lifestyle factors and health behaviors including MHT use, were obtained. 615 women reported current use of estrogen plus progestin formulations (E+P), of whom 343 used CEE+MPA; 266 used estrogens alone (E alone), with 148 using CEE. Fifteen EM were measured by liquid chromatography/mass spectrometry and analyses were conducted separately for each EM. EM differences between E alone and E+P users were assessed using inverse probability weighted linear regression. Primary analyses included women using any MHT formulation; secondary analyses were restricted to CEE users. Results: Compared to users of E+P, concentrations of all EM were higher in E alone users, and significantly so for unconjugated estrone, estradiol, 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol. Relative to total EM, concentrations of 2- and 4-pathway EM did not differ by MHT group (for E alone and E+P users, 2-pathway EM were ~14% of the total EM; 4-pathway EM were &amp;lt;2% of the total), but E+P users had a significantly higher proportion of 16-pathway EM compared to E alone users (32% vs. 30%, p=0.025). Similar patterns were observed in analyses comparing users of CEE alone to CEE+MPA, albeit not significant. Conclusion: Our data suggest that women using E alone may preferentially metabolize estrogens along the 2- and 4-hydroxylation pathways, whereas in E+P users, more extensive metabolism occurs along the 16-pathway. However, we did not observe these effects in the smaller groups of women using CEE alone or CEE+MPA, the MHT formulations administered in the treatment arms of the WHI trial. Our findings in E alone users are consistent with epidemiologic investigations demonstrating reduced breast cancer risk in postmenopausal women with more extensive 2-pathway estrogen metabolism, and may provide a clue to the breast cancer risk reduction observed in these women. Citation Format: Roni T. Falk, Garnet L. Anderson, Vanessa M. Barnabei, Louise A. Brinton, Jane A. Cauley, Chu Chen, Rowan T. Chlebowski, Sally B. Coburn, JoAnn E. Manson, Ruth M. Pfeiffer, Kerryn W. Reding, Thomas E. Rohan, Gloria E. Sarto, Nicolas Wentzensen, Britton Trabert. Estrogen metabolism in menopausal hormone users: Does it differ between estrogen plus progestin and estrogen alone users in the Women’s Health Initiative Observational Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4237. doi:10.1158/1538-7445.AM2017-4237

Then and Now: Experts Insights on Understanding the Women's Health Initiative Hormone Therapy Trials [4M

INTRODUCTION: More than a decade following publication of the Women's Health Initiative (WHI) clinical trials for hormone therapy (HT), perception in the medical community remains that HT is unsafe for postmenopausal women. The evidence suggests otherwise for the majority of symptomatic menopausal women under 60 years and within 10 years of menopause. METHODS: A 30-minute expert interview CME program discussed the accurate interpretation of data from the WHI trials. Correct answers were compared between immediate pre- and post-tests, including case-based scenarios. RESULTS: 15,236 participants have engaged with the program to date (July 1–August 31, 2016) with 355 completions. Participants included physicians, 50%, and nurses, 21%, with 31% in women's health, 30% in primary care and the rest distributed among other specialties. Correct responses improved from pre- to post-test for all questions, including outcomes from the WHI trials (22%-52% to 49%-88%), attributes of new menopausal medications (43% to 67%) and appropriate application of clinical guidelines (64% to 90%). For most case-based questions, responses improved from 58%-83% in the pre-test to 78%-96% in the post-test, with one question in older postmenopausal women (aged 62) only improving from 42% to 48%. CONCLUSION: Results demonstrate the negative impact of inappropriate data interpretation, its effect on clinical care and guideline application. Continued uncertainty remains regarding HT risks, interpretation of follow-up studies, and the benefits/risks of newer medications. Future educational efforts must reinforce the need to treat symptomatic menopausal women according to the best available evidence, and how benefits exceed risks for many women with existing/new HT medications.