Therapy In Postmenopausal Women Research Articles

Abstract 2840: CDK4/6 inhibitor PD-0332991 (palbociclib) promotes cell death and synergizes with CPT-11 in colorectal cancer under hypoxia in vitro

Abstract We recently reported that a family of nucleoside analogues (sangivamycin-like molecules) can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK3-beta (Mayes et al., Cancer Research, 2011). We further reported that CDK inhibitors can destabilize HIF1-alpha regardless of VHL or p53 status or the presence of hypoxia (Warfel et al., Cell Cycle, 2013). In order to translate this knowledge into a cancer therapeutic strategy, we investigated the effects of CDK inhibition in colorectal cancer (CRC) cell lines with or without chemotherapy. PD-0332991 (Palbociclib) is a specific inhibitor of CDK4/6 that has been tested in numerous clinical trials for breast cancer, NSCLC, GBM, lymphoma, leukemia, in combination with 5-FU and oxaliplatin in solid malignancies (NCT01522989) or with cetuximab in head and neck cancer (NCT02101034). Palbociclib was approved by the FDA in 2015 in combination with letrozole as initial endocrine therapy for post-menopausal women with ER(+)/Her2(-) breast cancer. Little is known about the effects of CDK4/6 inhibition in CRC. We investigated the therapeutic effect and anti-proliferative mechanism of CDK4/6 inhibition in CRC. We used CellTiter-Glo assays to detect CRC cell viability and determined IC50 values (50% inhibitory concentration) of single drug through nonlinear regression analysis by GraphPad Prism software. The combination index (CI) of multiple drug combinations was identified with Compusyn analysis. We found that Palbociclib promotes cell death of CRC cells under hypoxia but not under normoxia where Palbociclib inhibited cell proliferation via the pRb pathway. These results suggest that the CDK4/6 inhibitor could regulate cell fate of CRC via different molecular mechanisms under hypoxia versus normoxia. We further found that Palbociclib can upregulate ERK/MAPK signaling under hypoxia, as compared with normoxia. The IC50 values of Palbociclib were generally higher under hypoxia (Mean ± SD: 10.54 ± 3.35 μM, N = 5) versus normoxia (Mean ± SD: 6.61 ± 0.85 μM, N = 5) in CRC cell lines. Thus, hypoxia promotes resistance of CRC cells toward the cytotoxic activity of the CDK4/6 inhibitor. We found that Palbociclib synergizes with CPT-11 much better than with either 5-FU or oxaliplatin against CRC cell lines with different molecular subtypes. Based on our findings that Palbociclib can promote cell death of CRC cells under hypoxia and synergizes with CPT11, further investigation is needed to assess the novel combination therapy against CRC. Citation Format: Jun Zhang, Lanlan Zhou, Shuai Zhao, David Dicker, Wafik S. El-Deiry. CDK4/6 inhibitor PD-0332991 (palbociclib) promotes cell death and synergizes with CPT-11 in colorectal cancer under hypoxia in vitro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2840.

Extended AI Therapy in Postmenopausal Women With Early Breast Cancer

Extended AI Therapy in Postmenopausal Women With Early Breast Cancer

Endocrine therapy for postmenopausal women with hormone receptor positive in advanced breast cancer

With the emergence of new endocrine drugs and the development of research in resistance mechanisms, significant progress has been achieved in the endocrine treatment of breast cancer in recent years. Fulvestrant, the combination of endocrine drugs and the combination of targeted therapy with endocrine therapy will be effective treatments for postmenopausal women with hormone receptor positive in advanced breast cancer. Key words: Breast neoplasms; Receptors, estrogen; Therapy

Postmenopausal Hormone Therapy and Risk of Stroke: Impact of the Route of Estrogen Administration and Type of Progestogen.

The benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens. We set up a nested case-control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01-2.49) in oral estrogen users and 0.83 (0.56-1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49-1.26), pregnanes (OR, 1.00; 95% CI, 0.60-1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62-2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05-4.81). Both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.

Ocular Surface Disease in Breast Cancer Patients Using Aromatase Inhibitors

Aromatase inhibitors (AIs) are widely used as adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. The purpose of this study was to investigate the potential impact of AIs on the anterior segment of the eye and especially the ocular surface. Participants in our study were 41 hormone receptor-positive early stage breast cancer patients (80 eyes), treated with AIs, while 80 eyes of 40 age- and gender-matched healthy controls, not previously used AIs for any purpose, were also evaluated. All participants underwent a complete ophthalmological examination, including best corrected visual acuity (BCVA) assessment, slit-lamp biomicroscopy, and dilated fundus examination. Ocular surface disease-related symptoms and signs were also recorded. The most common symptom was found to be blurred vision, while other symptoms included foreign body sensation, tearing, redness, and photophobia. Slit-lamp examination revealed blepharitis and meibomian gland dysfunction in 75% and 42.5% of patients, respectively. Superficial punctate keratitis and conjunctival injection were also present. Our results demonstrated a high prevalence of ocular surface disease-related symptoms and signs in patients receiving AIs compared to healthy controls. This study may raise a flag regarding the use of AIs. However, further and larger prospective longitudinal studies are needed to examine the possible effect of AIs alone or in combination with chemotherapy in the eyes of breast cancer patients.

Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium.

Endometrial cancer develops during exposure to estrogen unopposed by progesterone. Traditional formulations for menopausal hormone therapy include a progestin in women with a uterus. However, progestin exposure increases breast cancer risk in postmenopausal women. Alternatives to progestin include bazedoxifene (BZA), a selective estrogen receptor modulator, which prevents estrogen induced endometrial hyperplasia in clinical trials. Molecular mechanisms responsible for BZA's antiproliferative effect are not fully elucidated. We profiled endometrial adenocarcinoma, hyperplasia, and normal proliferative endometrium for differential expression in genes known to be regulated by estrogens or progesterone. Fibroblast growth factor (FGF)18, a paracrine growth factor promoting epithelial proliferation, was significantly increased in adenocarcinoma. Progesterone represses FGF18 by inducing heart and neural crest derivatives expressed transcript 2 (HAND2) in stromal cells. Notably, we confirmed lower HAND2 mRNA in adenocarcinoma, along with higher FGF tyrosine kinase receptor 2 and E74-like factor 5, collectively promoting FGF18 activity. We hypothesized BZA reduces epithelial proliferation by inhibiting FGF18 synthesis in stromal cells. To determine whether BZA regulates FGF18, we treated primary stromal cells with BZA or vehicle. In vitro, BZA reduced FGF18, but did not affect, HAND2. CD1 female mice received either BZA, conjugated estrogen (CE), or combined BZA/CE for 8 weeks. CE-treated mice had nearly 3-fold higher FGF18 expression. In contrast, BZA-treated mice, alone or with CE, had similar FGF18 as controls. Unexpectedly, BZA, alone or with CE, reduced HAND2 more than 80%, differing from progesterone regulation. Reduction of FGF18 is a potential mechanism by which BZA reduces endometrial proliferation and hyperplasia induced by estrogens. However, BZA works independently of HAND2, revealing a novel mechanism for progestin-free hormone therapy in postmenopausal women.

Adjuvant endocrine therapy for post-menopausal women with ductal carcinoma in situ—is the pain worth the gain?—a commentary on the NSABP-B35 trial

The recent publication of the NSABP-B35 trial provides important information about the relative value of anastrozole (ANA) over tamoxifen (TAM) for post-menopausal women with ductal carcinoma in situ (DCIS) treated with conservative surgery (CS) and radiotherapy (RT). However, the clinician is still left wondering when adjuvant hormonal treatment (HT) should be prescribed for the individual patient and now whether to use ANA instead of TAM (1).

Changes in bone mineral density during 5 years of adjuvant exemestane therapy in postmenopausal women with early breast cancer.

e12003Background: Adjuvant therapy with aromatase inhibitors (AI) is associated with increased bone loss in postmenopausal women. The effect of 5 years of treatment with anastrozole on bone mineral...

Dynamics of the main parameters of structure-functional condition of the left ventricle myocardium in usage of combination antihypertension therapy for postmenopausal women with different obesity patterns

Aim. To assess the dynamics of the main structural and functional parameters of the left ventricle myocardium condition (LV) in postmenopausal women with arterial hypertension (AH) and different types of obesity: abdominal (AO) and gluteofemoral (GFO), taking combination hypotensive therapy: angiotensin-converting enzyme inhibitor (ACEi) or direct renin inhibitor (DRI). Material and methods. Totally, 168 women studied with AH in postmenopause: 97 with AO and 71 with GFO. Women with different obesity types were randomized to therapy groups as ACEi+diuretic and DRI+diuretic. Follow-up lasted for 24 weeks. Results. Combination therapy that included DRI, led to target values of BP in 90,2% of patients with AO and 90,9% with GFO. Usage of DRI in AO and GFO was followed by significant decrease of wall thickness, left ventricle myocardium mass (MMLV) — by 22,6% and 17,9%, MMLV index — by 23,1% and 18,8%, respectively, (р<0,05), and parameters of diastolic function of LV. On therapy by ACEi+diuretic target values of BP were recorded in 71,4% of AO patients, and in 84,4% with GFO. In 24 weeks of ACEi usage with diuretic in AO and GFO, there was significant change of diastolic LV function (p<0,05). Comparative analysis showed that DRI therapy was better comparing to ACEi in AO patients with AO in the sense of the LV structural-functional improvement. Conclusion. Usage of ACEi or DRI in combination with diuretic in postmenopause led to significant cardioprotection not depending on obesity type. In addition, in AO the usage of DRI+diuretic was advantageous comparing to ACEi+diuretic in the sense of hypertrophy regression and LV diastolic function improvement.

Neoadjuvant chemotherapy versus neoadjuvant endocrine therapy in postmenopausal women with ER+ Her2- breast cancer and axillary involvement

Neoadjuvant chemotherapy versus neoadjuvant endocrine therapy in postmenopausal women with ER+ Her2- breast cancer and axillary involvement

The circulating sphingosine-1-phosphate level predicts incident fracture in postmenopausal women: a 3.5-year follow-up observation study.

A high level of circulating sphingosine-1-phosphate (S1P) is associated with a high incidence of osteoporotic fracture and a high rate of an insufficient response to bisphosphonate therapy. Sphingosine-1-phosphate (S1P) is a significant regulator of bone metabolism. Recently, we found that a high plasma S1P level is associated with low bone mineral density (BMD), high levels of bone resorption markers (BRMs), and a high risk of prevalent vertebral fracture in postmenopausal women. We investigated the possibility that S1P is a predictor of incident fracture. A total of 248 postmenopausal women participated in this longitudinal study and were followed up for a mean duration of 3.5years (untreated [n = 76] or treated with bisphosphonate or hormone replacement therapy [n = 172]). The baseline plasma S1P level and prevalent and incident fracture occurrence were assessed. A high S1P level was significantly associated with a higher rate of prevalent fracture after adjusting for femoral neck (FN) BMD, BRM, and potential confounders (odds ratio = 2.05; 95% confidence interval [CI] = 1.03-4.00). Incident fractures occurred more frequently in the highest S1P tertile (T3) than in the lower two tertiles (T1-2) after adjusting for confounders, including baseline FN BMD, prevalent fracture, antiosteoporotic medication, annualized changes in FN BMD, BRM, and potential confounders (hazard ratio = 5.52; 95% CI = 1.04-56.54). Insufficient response to bisphosphonate therapy occurred more frequently in T3 than T1-2 (odds ratio = 4.43; 95% CI = 1.02-21.25). The plasma S1P level may be a potential predictor of fracture occurrence and an insufficient response to bisphosphonate therapy in postmenopausal women.

Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy

Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors. We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053). Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy.

Effects of Hormone Therapy on Intraocular Pressure: The Women's Health Initiative-Sight Exam Study

Previous studies suggest that hormone therapy favorably affects intraocular pressure (IOP). Here, we examined the association between hormone therapy use and IOP in the context of a large randomized trial. Secondary data analysis from a randomized controlled trial. We used data from the Women's Health Initiative-Sight Exam (WHISE). Women with prior hysterectomy received oral conjugated equine estrogen (0.625mg/day) or placebo. Women with a uterus received estrogen plus progestin (medroxyprogesterone acetate 2.5mg/day) or placebo. IOP was measured 5 years after randomization. Adjusted linear regression models were used to assess the association between hormone therapy and IOP. The WHISE included 1668 women in the estrogen-alone trial (aged 63-86, mean 72 years) and 2679 women in the estrogen-plus-progestin trial (aged 63-87, mean 72 years). In multivariate analyses, compared to placebo treatment, treatment with estrogen alone was associated with a 0.5mm Hg reduction of the IOP in the right eye (95% CI:-0.8,-0.1, P= .005) and a 0.6mm Hg (95% CI:-0.9,-0.3, P < .001) reduction of the IOP in the left eye. In the estrogen-plus-progestin trial, there was no significant difference in IOP between the treatment and placebo groups (P= .30 right eye and P= .43 left eye). This study represents an IOP analysis in the largest hormone trial available. Estrogen-alone therapy in postmenopausal women is associated with a small but significant IOP reduction of 0.5mm Hg. The clinical significance of this small decrease remains to be determined.

Abstract P5-13-03: Fulvestrant plus anastrozole as neoadjuvant therapy in postmenopausal women with hormone receptor positive early breast cancer

Abstract Background: Aromatase inhibitors (AIs) are effective in reducing the risk of recurrence from breast cancer (BC) but 20% of patients (pts) with early BC still recur despite adjuvant AIs. Thus more effective endocrine therapies (HTs) are needed. In metastatic BC (MBC), combination of lower dose fulvestrant plus anastrozole improves survival compared to anastrozole alone. The 21-gene Recurrence Score® (RS; Oncotype DX®) has been validated to predict benefit from adding chemotherapy (CT) to HT where pts with a low score have little benefit from CT and derive a large benefit from HT. Ki-67 response to neo-adjuvant HT may predict adjuvant outcomes to HT. Postoperative Endocrine Prognostic Index (PEPI) and modified PEPI may further identify a subset of HT sensitive cancers that do not require adjuvant CT (PEPI 0 category). We conducted a single arm phase II trial to assess the efficacy of fulvestrant plus anastrozole as neoadjuvant HT in pts with operable BC. Methods: Postmenopausal pts with stage II and III, ER/PR+, HER2 (-) BC with a RS&amp;lt;25 (performed on initial core bx) were included. Duration of neo-adjuvant HT was 4 months. Pts received anastrozole 1mg (PO) daily continuously from day 1 until surgery + fulvestrant (IM) 500mg on day 1, 14 and 28 of cycle 1, and on the last day of three subsequent 28 day cycles (total 6 doses of fulvestrant). At week 4, an optional core bx was repeated to assess change in Ki-67. Response assessments were made clinically every 4 wks. All pts had breast/axillary surgery after the 6th dose of fulvestrant. Ki-67, histologic grade, ER/PR status, and RS were assessed at baseline, core bx at 4 wks, and at definitive surgery. Primary end points were pathologic complete response (pCR) rate and change in Ki-67. Adjuvant CT was left to the discretion of treating physician. Results: 42 pts were enrolled 7/2009 to 11/2014. Median age was 62. 32 (76%) patients had stage IIA, 7 (17%) had stage IIB and 3 (7%) had stage III disease. 14% had clinically node positive disease. The median RS was 12 (0-24). Median tumor size was 3.5cm. 21%, 74%, and 5% had grade 1, 2 and 3 tumors respectively. Mean ER expression was 95%. 16 (38%) pts had a clinical complete response (cCR), 13 (31%) had a clinical partial response (cPR) and 12 (29%) had stable disease. One pt had progression on therapy. There were no pCRs. Median baseline Ki-67 was 5% (1-36%). 94% of pts had decrease in Ki-67 from baseline to 4-week bx and 97% of pts had decrease in Ki-67 from baseline to surgery. Modified PEPI score at surgery was 0 in 53% of patients. 78% of pts did not receive adjuvant CT. At median follow up of 38 mos only 1 pt had a recurrence with 98% free of a recurrence. There were no grade 3 or grade 4 toxicities. Conclusions: The neoadjuvant combination of anastrozole and fulvestrant in pts with RS&amp;lt;25 markedly improves Ki-67 response with more than half of pts achieving a modified PEPI score of 0 at surgery. At a relatively short median follow up, recurrence rate is very low. Given the efficacy and tolerability of anastrozole plus fulvestrant in MBC and now in the neo-adjuvant setting, an adjuvant trial of this combination is warranted in pts with ER+ BC. Citation Format: Khan QJ, Barr JA, Britt AS, Kimler BF, Connor CS, McGinness M, Mammen JMV, Wagner JL, Amin A, Springer M, Baccaray S, Fabian CJ, Sing AP, Sharma P. Fulvestrant plus anastrozole as neoadjuvant therapy in postmenopausal women with hormone receptor positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-13-03.

Targeted Combinations for Hormone Receptor–Positive Advanced Breast Cancer: Who Benefits?

Although endocrine therapy is an effective strategy for patients with hormone receptor–positive (HR-positive) locally advanced, metastatic breast cancer (MBC), not all patients respond to first-line treatment because of primary, de novo resistance; those who do respond subsequently progress with secondary, acquired resistance. Significant progress has been made in understanding the molecular signaling pathways that account for endocrine resistance, and in recent years, this has led to various targeted combination strategies aimed at reversing or preventing endocrine resistance. One of the key signaling pathways in HR-positive breast cancer is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and indeed, good evidence suggests that this pathway becomes activated during secondary endocrine resistance in HRpositive breast cancer. As such, the BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) study in endocrine-resistant MBC demonstrated a significant improvement in progression-free survival (PFS) for mTOR antagonist everolimus in combination with steroidal aromatase inactivator exemestane compared with exemestane alone in 724 postmenopausal women with HR-positive MBC after progression on a nonsteroidal aromatase inhibitor (median PFS, 7.8 versus 3.2 months; hazard ratio, 0.45; log-rank P , .001). This clinically relevant improvement in PFSwas sufficient for regulatory approval to be granted in 2012 for this targeted combination to become a new standard of care for the treatment of endocrine-resistant postmenopausal breast cancer. The key questions when considering targeted combination treatment for HR-positive MBC are who benefits most from this approach and what the best setting is in which to use this strategy. For example, would a combination of an mTOR inhibitor with endocrine therapy only be effective in the second-line setting for endocrine-resistant MBC, or could this option delay or prevent endocrine resistance from developing in the first-line endocrinesensitive setting? The HORIZON (Letrozole Plus Oral Temsirolimus as First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer) trial of the oral mTOR antagonist temsirolimus in combination with letrozole in the first-line setting showed no benefit compared with letrozole plus placebo in 1,112 patients with HR-positive MBC, 60% of whom were endocrine therapy naive. One explanation for this result, which contrasts with BOLERO-2, could be that the PI3K/Akt/mTOR cell survival pathway is not operative in all endocrine-sensitive estrogen receptor (ER) –positive breast cancer cells, only becoming switched on during the development of acquired secondary resistance. Therefore, at the present time, clinical data only support a role for mTOR therapy for endocrine-pretreated HR-positive MBC. Identifying biomarkers that might help to predict which patients will derive the greatest clinical benefit from costly and potentially more toxic targeted therapies in HR-positive MBC is an important research priority. The lesson from the success of trastuzumab in HER2-positive MBC was the reliable identification of the oncogenic driver in this disease subset, namely HER2 gene amplification. To date, a similar goal has proven elusive for targeted combination strategies in a more heterogenous population of patients with HR-positive MBC. In the article accompanying this editorial, Hortobagyi et al report the first HER2 correlative analysis of genomic alterations, as determined by next-generation sequencing, with clinical efficacy for the targeted combination of everolimus and exemestane from a subset of representative patients with HRpositive MBC treated within the randomized, placebo-controlled BOLERO-2 study. The authors tested a reasonable mechanistic hypothesis that tumors addicted to a hyperactive PI3K/mTOR pathway might derive greater benefit from everolimus. Although this retrospective analysis was conducted predominantly on archival primary, rather than real-time, metastatic tumors, the premise was that key activating mutations within the original primary tumor may have primed the disease for relapse on endocrine therapy and that these mutations represent a reasonable target for therapy in the endocrine-resistant second-line setting. The results showed, perhaps disappointingly, that mutations in PIK3CA or the PI3K/Akt/mTOR pathway as a whole were not associated with everolimus efficacy, although subgroup analysis did suggest a greater PFS benefit from everolimus in patients with exon 9 compared with exon 20 mutations, a finding first reported in a neoadjuvant study of everolimus with letrozole. This specific finding could relate to different activating mutations of PIK3CA regulating Akt-mediated tumor cell survival and differential responses to mTOR antagonism. Whether PIK3CA mutations, which represent the most common genomic alteration in HR-positive breast cancer, will be any more predictive for benefit from specific PI3K inhibitors remains to be determined. Several pan-isoform inhibitors that target the PI3K/Akt pathway upstream of mTOR, including buparlisib (BKM-120) and pictilisib (GDC-0941), are currently being tested in endocrine-resistant MBC in similarly designed studies to BOLERO-2, both with prospective stratification/selection for PIK3CA mutation status. Although preliminary results for pictilisib in the phase II FERGI (Fulvestrant in

Phytoestrogen-Rich Dietary Supplements in Anti-Atherosclerotic Therapy in Postmenopausal Women.

Cardiovascular diseases remain the leading cause of morbidity and mortality among postmenopausal women in western societies. There are still no specific and highly efficient methods of preservation of women's vascular health in modern preventive medicine. For many years physicians have assumed that hormone replacement therapy prevents the development of atherosclerosis in menopausal women. However, the results of the largest international trials involving thousands of women have completely destroyed this hope. The modern perspective for the development of effective and safe drugs to enhance the quality of life and to prevent atherosclerosis progression in postmenopausal women may be the use of phytoestrogens, the substances of plant origin possessing estrogen- like effects, and possibly providing anti-atherosclerotic and anti-climacteric action. Phytoestrogens are often considered as a possible alternative to hormone replacement therapy, since they are believed to alleviate some symptoms of menopause. However, until now there is no exact evidence to consider phytoestrogens as the substances that protect women from atherosclerosis. It should be noted that the data from clinical studies with inconsistent results are mainly inconsistent per se, as most of the studies have serious limitations due to the study design and the participants' compliance. Nevertheless, there is a substantial evidence that phytoestrogens have the potential to address several conditions and diseases associated with the menopausal transition. Phytoestrogens, at least, can potentially reduce atherosclerosis and atherosclerosis-related diseases through multiple mechanisms, by regulating serum lipid metabolism, arterial vessels, cytokine levels, and coagulation/fibrinolysis system. However, a skepticism exists concerning the true potential of phytoestrogens to beneficially modify these processes. An analysis of findings from supplementing the diet with phytoestrogens has failed, in general, to confirm them as the agents responsible for beneficial cardiovascular effects. Fortunalely, now there is a growing interest to the use of phytoestrogens for primary prevention of cardiovascular disease in postmenopausal women. Clinical and epidemiologic data indicate that phytoestrogens possess anti-atherosclerotic effects and may be used to prevent and treat cardiovascular diseases, and that adding phytoestrogens to the diet can contribute to the health of postmenopausal women. This review discusses the effects of phytoestrogens possibly beneficial for cardiovascular health, and how these effects could retard the progression of atherosclerosis, as well as the areas that need further investigation.

Benefit/risk for adjuvant breast cancer therapy with tamoxifen or aromatase inhibitor use by age, and race/ethnicity.

In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women's Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta-analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances.

One-year treatment persistence with local estrogen therapy in postmenopausal women diagnosed as having vaginal atrophy.

Estrogen therapy is considered to be the most effective treatment of vaginal atrophy (VA) symptoms. This retrospective study compares rates of pharmacy refill-based treatment persistence in women treated for VA with local estrogen therapy (LET) creams versus low-dose vaginally administered tablets. Study cohort included treatment-naive women aged 45 years or older within the IMS PharMetrics Plus claims database who filled one or more prescriptions for a LET cream or tablet between January 1, 2010 and September 30, 2012. Index LET was the first observed LET claim in pharmacy records. Persistence was defined as the number of consecutive days of treatment available of the index LET during the 12-month follow-up period. In adjusted analyses, we compared the risks of discontinuation of index therapy. Of 30,197 women eligible for analysis, 12,187 (40.4%) initiated treatment with conjugated estrogens vaginal cream, 11,574 (38.3%) initiated treatment with estradiol vaginal cream, and 6,436 (21.3%) initiated treatment with 10-μg vaginal estradiol tablets (formulation introduced in 2010). Cohorts were comparable on age, geography, and baseline comorbidities. During the 12-month follow-up period, 86.2% to 89.4% of cream users discontinued LET after the first prescription compared with 57.8% of tablet users (P < 0.0001). A greater proportion of tablet initiators than cream users were fully (100%) persistent during the 12-month follow-up period. Mean treatment duration was 103.4 days for tablets versus 44.6 to 48.1 days for creams (P < 0.0001). After adjustment for baseline characteristics, tablet initiators had a lower risk of discontinuation compared with cream users (P < 0.0001). Low-dose LET tablets, compared with cream formulations, are associated with greater persistence in the treatment of VA.

Patterns of resource utilization and cost for postmenopausal women with hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer in Europe.

BackgroundHealthcare resource utilization in breast cancer varies by disease characteristics and treatment choices. However, lack of clarity in guidelines can result in varied interpretation and heterogeneous treatment management and costs. In Europe, the extent of this variability is unclear. Therefore, evaluation of chemotherapy use and costs versus hormone therapy across Europe is needed.MethodsThis retrospective chart review (N = 355) examined primarily direct costs for chemotherapy versus hormone therapy in postmenopausal women with hormone-receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer across 5 European countries (France, Germany, The Netherlands, Belgium, and Sweden).ResultsTotal direct costs across the first 3 treatment lines were approximately €10 000 to €14 000 lower for an additional line of hormone therapy-based treatment versus switching to chemotherapy-based treatment. Direct cost difference between chemotherapy-based and hormone therapy-based regimens was approximately €1900 to €2500 per month. Chemotherapy-based regimens were associated with increased resource utilization (managing side effects; concomitant targeted therapy use; and increased frequencies of hospitalizations, provider visits, and monitoring tests). The proportion of patients taking sick leave doubled after switching from hormone therapy to chemotherapy.ConclusionsThese results suggest chemotherapy is associated with increased direct costs and potentially with increased indirect costs (lower productivity of working patients) versus hormone therapy in HR+, HER2– advanced breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1762-3) contains supplementary material, which is available to authorized users.

Incidence of endometrial spotting or bleeding during continuous-combined estrogen-progestin therapy in postmenopausal women with and without hypertension.

Endometrial spotting or bleeding is a common adverse effect among women taking continuous-combined estrogen-progestin therapy. The renin-angiotensin-aldosterone system plays a major role in hypertension and is present in the endometrium. We hypothesized that postmenopausal women with hypertension would have a higher incidence of bleeding compared with postmenopausal women without hypertension. A multivariate mixed-effects logistic model estimated the odds ratios for the relationship of hypertension status or use of antihypertensive drugs with endometrial bleeding using the Women's Health Initiative database. The incidence of spotting or bleeding in the first 12 months of estrogen-progestin use was 42% in women aged 50 to 79 years. Women with hypertension were more likely to experience bleeding than women without hypertension (odds ratio, 1.07; 95% CI, 1.02-1.13). Overall antihypertensive medication use increased bleeding with an odds ratio of 1.24, whereas angiotensin II receptor antagonists had a reduced odds ratio (0.53). Postmenopausal women with hypertension are more likely to bleed than postmenopausal women without hypertension when taking continuous estrogen-progestin, with less bleeding in women using angiotensin II receptor antagonists. This finding is novel and supports our hypothesis that the endometrial renin-angiotensin-aldosterone system may contribute to endometrial bleeding.