PM Women Research Articles

Maternal care experience and postpartum depressive symptoms among migrant and native in Portugal

Abstract Background Migration is a risk factor for both, poor maternal experience with healthcare services (MEHCS) and postpartum depressive symptoms (PPDS), a matter of concern due to their adverse consequences. We aimed to assess the association between MEHCS and PPDS taking into account the migration status. Methods This is part of a population-based study (baMBINO project), enrolling native (PT; n = 1568), permanent migrant (PM; n = 676) and temporary migrant (TM; n = 757) women recruited at delivery (2017-2019) in 32 Portuguese public hospitals. MEHCS was assessed based on 39 items of the Migrant Friendly Maternal Care Questionnaire asking about how women have experienced maternal care during pregnancy, during delivery and after birth. Items were grouped into 9 components each one assessing a different issue of MEHCS. For each component women were classified as having “good” or “less than good” experience. PPDS were assessed using the Edinburgh Postnatal Depression Scale (cut-off≥12). Multivariate logistic regression model was fitted to estimate the association between MEHCS and PPDS. Adjusted odds ratio (aOR) and respective 95% confidence interval were obtained. Results PPDS were reported by 3.8%, 5.8% and 8.2% of PT, PM and TM women, respectively (p < 0.001). After adjustment, 4 out 9 components of MEHCS appeared related with PPDS, such that women reporting less than good experience with “understanding information” (aOR=1.72 95%CI:1.14-2.60), “decisions according to maternal wishes” (aOR=1.56 95% CI:1.04-2.34), “time waiting for healthcare” (aOR=1.50 95%CI:1.04-2.18) and “healthcare provider's attitudes during pregnancy” (aOR=1.58 95%CI:1.01-2.47) showed higher odds of PPDS than women reporting good experience. Conclusions Further than the migration status, poor experience with some issues of maternal care seems play a role in the risk of PPDS Key messages

Therapy with vitamin D metabolits of structural and functional changes in bone tissue of working postmenopausal women with ostearcopenia

The prevalence of osteoporosis and vitamin D deficiency in postmenopausal women working under harmful labour conditions has been examined. Reduced bone mineral density was revealed in 85% of the persons under observation, the incidence of OP was 35%, sarcopenia (SP) - 35%. Vitamin D deficiency was found in 91.3% of the workers, at the same time severe VD deficiency was observed in 32.9%, VD deficiency - in 7.5%, and the optimal level of vitamin D was observed in 1.2% of cases. 79 PM women with OP aged 50 - 60 y. o. (mean age - (55.7 ± 0.9) years), working at harmful conditions of the working environment with an average length of service 26.14 ± 0.91 years have been examined. Clinical group A (n = 30) received cholecalciferol at a dose of 2000 IU (4 drops) per day and alfacalcidol 1 μg (1 capsule) once a day for a year. This resulted in a positive effect on the level of 25(OH)D. The complex appointment of cholecalciferol and alfacalcidol reduced the level of PTH and confirmed the role of VD deficiency in the progress of secondary hyperparathyroidism. The data obtained revealed a slowing of the effect of VD on osteoclastogenesis. Decrease of bone resorption marker CTx in the women under examination confirmed the latter.

Association of Metabolic Syndrome with the Number of Breastfed Children in Postmenopausal Korean Women.

Metabolic syndrome is closely related to cardiovascular disease, and the prevalence of metabolic syndrome in postmenopausal women is increasing rapidly. The purpose of this study is to investigate the association between the number of breastfed children and the risk factors for metabolic syndrome in postmenopausal women and to evaluate the association between metabolic syndrome and bone mineral density and body composition variables in postmenopausal women depending on the number of breastfed children Methods: Data from KNHANES V-1 and 2 (2010-2011) were used, and a total of 939 postmenopausal women with 1 to 6 breastfed children aged 65-80 years participated in this study. We divided these women into three groups (group1 with 1-2, group2 with 3-4, group3 with 5-6) depending on the number of breastfed children Results: In the analysis of the associations between metabolic syndrome and its risk factors, highdensity lipoprotein cholesterol was the most negatively strongly associated with group1 (OR=0.103 [0.047-0.225]), triglyceride showed the highest association with group2 (OR=7.760 [3.770-15.97]) and group3 (OR=7.668 [4.102-14.33]). The risk factors of metabolic syndrome except for highdensity lipoprotein cholesterol and triglyceride was not associated with group1. In contrast, all risk factors of metabolic syndrome displayed a high association with group2 and group3. The findings of the present study suggest that the number of breastfed children is significantly associated with a more significant number of risk factors of metabolic syndrome in postmenopausal women, and the association between metabolic syndrome and body composition variables may differ depending on the number of breastfed children.

Abstract P6-09-27: The EA2clin test significantly predicts response and survival in both pre and post-menopausal women with ER-positive breast cancers

Abstract Background Identifying breast cancer (BC) patients likely to recur on endocrine therapy (ET) is a challenge. Several methods and tests based on clinical parameters and multi-gene or protein classifiers have been shown to predict those likely to recur. Tests that incorporate baseline and on-treatment markers are likely to be more accurate than tests based on baseline characteristics alone. 4 genes were identified by microarray that predicted for to ET: 2 at diagnosis and 2 at 14 days. The EndoAdjuvant2 (EA2) test uses 2 of these genes: IL6ST at diagnosis and on-treatment MCM4 at transcript level or by graded immunohistochemistry (IHC). The aim of this study was to compare EA2 with currently used clinical parameters in 4 different cohorts of pre and postmenopausal women. Patients The cohorts are (1) 73 post-menopausal women (PMW) with ER+ BC treated with neoadjuvant letrozole (L) then surgery, (2) 39 PMW with ER+ BC treated with neoadjuvant anastrozole (A) then surgery, (3) 108 PMW who received 2-weeks of A or L prior to surgery (4) 25 preMW with ER+ BC who received one 750mg dose of fulvestrant prior to surgery. All had adjuvant ET and 5-10 years follow up. Neoadjuvant response was assessed by periodic 3D ultrasound. Results The 4 gene assay had 96% (training; cohort 1) and 93% (validation; cohort 2) accuracy of response prediction to neoadjuvant L or A. In cohort 1, clinical parameters were available. On univariate regression analysis intrinsic subtype (luminal A/B; defined using PAM50) (P=0.002), histological grade (P=0.033) and HER2 status (P=0.001) significantly predicted clinical response. EA2 out-performed all these in both univariate (P<0.0001) and multivariate regression analysis (P<0.0001). The final model only retained EA2 as significant. Node status, tumour size and PR expression were not associated with response to endocrine therapy. EA2 predicted recurrence free in cohorts 1 and 3 combined: RFS (P=0.0004, HR=17.63 95%CI: 4.95-17.6), BCSS (P=0.0007, HR=16.60: 3.36-45.7). The Nottingham Prognostic Index (NPI) also predicted RFS (P=0.0002) and BCSS (P=0.0017) in univariate analysis but in the Cox analysis NPI was not found to be significant, although in the low risk group there were only 1/46 events compared to 19/62 in the moderate/high risk group. Histological grade (P<0.0001), Ki67 (%) (P=0.02) and tumour size (P=0.007) were significant on univariate analysis. In the Cox regression analysis, only EA2 (P=0.012) and histological grade (P=0.016) were significant predictors of RFS and BCSS. Using EA2 and NPI together a high and low risk subgroup could be identified. In the Cox regression analysis, combined EA2 plus NPI (EA2clin) outperformed both NPI and EA2 alone. EA2clin was validated in cohort 4 and predicted RFS (P=0.002, HR=8.43 95%CI: 2.18-32.53) and BCSS (P=0.008, HR=10.95 95%CI: 1.48-64.9). Conclusions • EA2 predicts clinical response, RFS and BCSS • EA2clin combines NPI and EA2, outperforms either alone and predicts outcome in a new validation cohort of preMW treated with Fulvestrant • EA2clin works in preM and PM women regardless of ET. Citation Format: Turnbull AK, Pearce DA, Arthur LM, Martinez-Perez C, Thomas JS, Fernando A, Renshaw L, Sims AH, Dixon JM. The EA2clin test significantly predicts response and survival in both pre and post-menopausal women with ER-positive breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-27.

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women.

To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women. A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels. We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p = 0.006 to 0.037; odds ratio = 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p < 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women. This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families.

High Avidity Antibodies to Full-Length VAR2CSA Correlate with Absence of Placental Malaria

VAR2CSA mediates sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, increasing the risk of poor pregnancy outcomes. Naturally acquired antibodies (Ab) to placental parasites at delivery have been associated with improved pregnancy outcomes, but Ab levels and how early in pregnancy Ab must be present in order to eliminate placental parasites before delivery remains unknown. Antibodies to individual Duffy-binding like domains of VAR2CSA have been studied, but the domains lack many of the conformational epitopes present in full-length VAR2CSA (FV2). Thus, the purpose of this study was to describe the acquisition of Ab to FV2 in women residing in high and low transmission areas and determine how Ab levels during pregnancy correlate with clearance of placental parasites. Plasma samples collected monthly throughout pregnancy from pregnant women living in high and low transmission areas in Cameroon were evaluated for Ab to FV2 and the proportion of high avidity Ab (i.e., Ab that remain bound in the presence of 3M NH4SCN) was assessed. Ab levels and proportion of high avidity Ab were compared between women with placental malaria (PM+) and those without (PM−) at delivery. Results showed that PM− women had significantly higher Ab levels (p = 0.0047) and proportion of high avidity Ab (p = 0.0009) than PM+ women throughout pregnancy. Specifically, women with moderate to high Ab levels (>5,000 MFI) and those with ≥35% high avidity Ab at 5–6 months were found to have 2.3 (95% CI, 1.0–4.9) and 7.6-fold (p = 0.0013, 95% CI: 1.2–50.0) reduced risk of placental malaria, respectively. These data show that high levels of Ab to FV2, particularly those with high avidity for FV2, produced by mid-pregnancy are important in clearing parasites from the placenta. Both high Ab levels and proportion of high avidity Ab to FV2 may serve as correlates of protection for assessing immunity against placental malaria.

Quantitative ultrasound in the management of osteoporosis.

Bone mineral density (BMD) is one of the major determinants of bone strength and fracture risk (FR), but it is not the only determinant, and overlap exists in BMD values between patients with and without fractures. It is therefore important to improve the strategy in better detecting patients at high FR who will benefit from treatments (TT). Quantitative bone US(QUS) are portable and less expensive than DXA. Only few QUS measuring the heel have reached a sufficient level of validation to be routinely used. They usually measure the attenuation (BUA) and the velocity (SOS) of the US wave. It is well established that valid heel QUSs predict fragility fracture in PM women and men &amp;gt;65, independent of BMD. Then, heel QUS can be used in combination with other clinical risk factors (CRFs) in a model of risk assessment. Then, when DXA is available, the primary clinical use of heel QUS is to identify, in conjunction with CRF, a population at low FR in which no further diagnostic evaluation is necessary. On the other hand, if central DXA cannot be done, pharmacologic TT can be initiated if the probability, as assessed by heel QUS in conjunction with CRF, is sufficiently high.

Toward Optimal Treatment in Women: The Effect of Sex on Metoprolol‐Diphenhydramine Interaction

The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher S-metoprolol AUC(0-infinity) and 26% and 71% lower CL/F, respectively, compared to men with the same phenotype (all Ps < .05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P < .0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P < .009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps < .05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men.

Effect of Long‐Term Testosterone Administration on the Endometrium of Female‐to‐Male (FtM) Transsexuals

Long term safety of testosterone (T) administration in women is still unknown. In particular few and discordant data exists on the effects of T on the endometrium. The aim of this study was to investigate the effects of long-term T treatment on endometrium histology and proliferation in female to male transsexual subjects (FtM). We compared these endometria with those of young women in the proliferative phase (PM) of the cycle and with those of post menopausal women (M). Endometrial samples from 27 FtM treated with T (intramuscular injection of 100 mg Testoviron Depot /10 days for at least one year), 30 M undergoing vaginal hysterectomy, and 13 PM undergoing hysteroscopy for infertility problems were collected. Endometrial proliferation was evaluated on the basis of histopathology and expression of the proliferation marker Ki-67. Both M and PM women had not received any hormonal treatment for at least one year. Circulating total testosterone (TT), estradiol (E), progesterone (P), insulin and glucose levels were measured in FtM and PM subjects. FtM had received T for 33.6 +/- 21.3 months (mean +/- SD). In FtM subjects, histological analysis found inactive endometrium similar to the atrophic menopausal endometrium. The expression of Ki-67 in the glands, stroma and glands and stroma together was significantly (p < 0.0005) lower in FtM than in PM women and was similar in the FtM and M groups. Small polyps were detected in 5 of the 27 FtM subjects. In conclusion our data suggest that exogenous T administration does not stimulate endometrial proliferation in FtM transsexuals and indeed may have atrophic effects.

Increased Strength and Physical Performance with Eccentric Training in Women with Impaired Glucose Tolerance: A Pilot Study

Menopause is associated with both a loss of muscle mass and a worsening of insulin sensitivity (IS). Although eccentric resistance exercise (ECC) can effectively improve muscle mass over time, a single bout of ECC can worsen IS. This study assessed the effect of repeated ECC on IS, muscle mass, and function in postmenopausal women with impaired glucose tolerance (IGT). Sixteen PM women (aged 56 years +/- 6.4) with IGT were randomly assigned to a 12-week, knee extensor ECC program (n = 10) or a nonexercise control group (CON) (n = 6). Participants underwent hyperinsulinemic-euglycemic clamps, dual-energy x-ray (DEXA) absorptiometry, quadriceps strength assessment, 6-minute walk (6MW) tests, and an assessment of steps taken per day before and after training. ECC participants experienced greater increases in leg lean soft tissue mass (ECC, 0.41 kg; CON, -0.53 kg; p = 0.03), quadriceps strength (ECC, 9.3 kg force; CON, -2.9 kg force; p = 0.02), and 6MW distance (ECC, 56.4 meters; CON, 3.3 meters; p = 0.03) than CON participants and demonstrated a trend toward more steps taken per day posttraining (ECC, +1747 steps; CON, +339 steps; p = 0.10). IS was unchanged. This novel exercise improves muscle mass and function without worsening IS in postmenopausal women with IGT. Because it can be performed at low levels of exertion and improves muscle mass and function without impairing IS, ECC should be used to ameliorate muscle loss in physically inactive postmenopausal women. The impact of longer-term ECC on IS should be investigated. Demonstrating that ECC does not worsen IS in this population is significant because it has promise to combat the muscle-mediated impairments common in aging women.

Rosiglitazone Decreases Blood Pressure in Female Dahl Rats: Role of Nitric Oxide and Oxidative Stress

In women the prevalence of hypertension (HT) and salt‐sensitivity of blood pressure (BP) increases after menopause (PM). The peroxisome proliferator activator receptor gamma agonist, rosiglitazone (RO), reduces BP in humans and animals, including male Dahl salt‐sensitive rats (DS). We tested the hypothesis that RO decreases BP in intact (Int) and ovariectomized (Ovx) female DS by increasing nitric oxide (NO) and decreasing oxidative stress (OS). Int and Ovx DS (10 weeks; n=15/group) received low salt diet (LS: 0.3% NaCl) or LS+RO (100mg/kg diet) for 1 week and then challenged for 1 week to high salt (HS: 8% NaCl) or HS+RO. Urinary Nitrate/nitrite (N/N) and F2‐isoprostanes (F2Ip) were assessed on HS. On LS, telemetric BP was similar in Int and Ovx, and RO decreased BP to similar levels. On HS, BP increased to higher levels in Ovx than Int and RO decreased BP to similar levels in Int and Ovx. RO increased N/N only in Ovx. F2Ip were lower in Ovx than Int and not affected by RO. Our data suggest that in Ovx on HS, RO protects against the greater increase in BP, possibly by increasing NO bioavailability, and that OS plays no role in salt‐sensitivity of BP in female DS. RO may be a new therapeutic approach for treating HT in PM women (supported by NIH HL 66072, AHA 0725561B)

Patterns of care regarding adjuvant hormonal agents and treatment of bone health in postmenopausal women with breast cancer in community and academic centers before and after the availability of ATAC (Adjuvant Tamoxifen, Armidex or Combination) study

6621 Background: Results from the ATAC trial comparing Tamoxifen to the Aromatase inhibitors (AIs) anastrozole in PM women with early stage breast cancer were initially presented in San Antonio, Texas, in December 2001. ASCO issued guidelines for the adjuvant use of AIs in 2002, updated in 2003. We compared patterns of usage of adjuvant hormonal agents and bone health management before and after availability of the ATAC data in community versus academic centers. Methods: We conducted a retrospective analysis of 432 patients between 1999–2005 from group practices affiliated with two large community hospitals and one academic center. Data were collected from tumor registries regarding demographics, first-line hormonal agent choice, and use of bone density studies, vitamin D/calcium supplements and bisphosphonates. Results: Demographics were identical in both groups before and after January 2002. Before 2002, 96% of the patients were prescribed Tamoxifen in both community and academic centers. After the initial presentation of the ATAC data, 55.08% (65/118) of patients from the community centers versus only 17.11% (19/111) from the academic center were prescribed AIs (p=0.0001). Of the 84 patients who received an AI after January 2002, similar proportions of patients had baseline bone density scans (38.5% community vs. 36.8% academic; p=0.89) and follow up annual/biannual scans (33 % vs. 32%; p=0.85). In addition, similar proportions of patients on AIs were prescribed calcium/vitamin D supplements (47.4% vs. 52.6%; p=0.69) and bisphosphonates (36.8% vs. 21.05%; p=0.20) in community and academic centers, respectively. Conclusions: Community oncologists adopted AIs into clinical practice sooner than academic physicians on the basis of unpublished clinical trial results, even before ASCO published guidelines. Although patients on AIs are deemed to be at higher risk for bone fractures, fewer than 40% were evaluated with baseline or surveillance bone density scans in both community and academic practices. Similar proportions of patients received calcium/vitamin D supplements or bisphosphonates among centers. No significant financial relationships to disclose.

Autonomic modulation of heart rate of young and postmenopausal women undergoing estrogen therapy

The aim of the present study was to determine whether estrogen therapy (ET) reduces alterations of the autonomic control of heart rate (HR) due to hypoestrogenism and aging. Thirteen young (24 +/- 2.6 years), 10 postmenopausal (53 +/- 4.6 years) undergoing ET (PM-ET), and 14 postmenopausal (56 +/- 2.6 years) women not undergoing ET (PM) were studied. ET consisted of 0.625 mg/day conjugated equine estrogen. HR was recorded continuously for 8 min at rest in the supine and sitting positions. HR variability (HRV) was analyzed by time (SDNN and rMSSD indices) and frequency domain methods. Power spectral components are reported as normalized units (nu) at low (LF) and high (HF) frequencies, and as LF/HF ratio. Intergroup comparisons: SDNN index was higher in young (median: supine, 47 ms; sitting, 42 ms) than in PM-ET (33; 29 ms) and PM (31; 29 ms) women (P < 0.05). PM showed lower HFnu, higher LFnu and higher LF/HF ratio (supine: 44, 56, 1.29; sitting: 38, 62, 1.60) than the young group in the supine position (61, 39, 0.63) and the PM-ET group in the sitting position (57, 43, 0.75; P < 0.05). Intragroup comparisons: HR was lower in the supine than in the sitting position for all groups (P < 0.05). The HRV decrease from the supine to the sitting position was significant only in the young group. These results suggest that HRV decreases during aging. ET seems to attenuate this process, promoting a reduction in sympathetic activity on the heart and contributing to the cardioprotective effect of estrogen hormones.

Autonomic modulation of heart rate of young and postmenopausal women undergoing estrogen therapy

The aim of the present study was to determine whether estrogen therapy (ET) reduces alterations of the autonomic control of heart rate (HR) due to hypoestrogenism and aging. Thirteen young (24 ± 2.6 years), 10 postmenopausal (53 ± 4.6 years) undergoing ET (PM-ET), and 14 postmenopausal (56 ± 2.6 years) women not undergoing ET (PM) were studied. ET consisted of 0.625 mg/day conjugated equine estrogen. HR was recorded continuously for 8 min at rest in the supine and sitting positions. HR variability (HRV) was analyzed by time (SDNN and rMSSD indices) and frequency domain methods. Power spectral components are reported as normalized units (nu) at low (LF) and high (HF) frequencies, and as LF/HF ratio. Intergroup comparisons: SDNN index was higher in young (median: supine, 47 ms; sitting, 42 ms) than in PM-ET (33; 29 ms) and PM (31; 29 ms) women (P < 0.05). PM showed lower HFnu, higher LFnu and higher LF/HF ratio (supine: 44, 56, 1.29; sitting: 38, 62, 1.60) than the young group in the supine position (61, 39, 0.63) and the PM-ET group in the sitting position (57, 43, 0.75; P < 0.05). Intragroup comparisons: HR was lower in the supine than in the sitting position for all groups (P < 0.05). The HRV decrease from the supine to the sitting position was significant only in the young group. These results suggest that HRV decreases during aging. ET seems to attenuate this process, promoting a reduction in sympathetic activity on the heart and contributing to the cardioprotective effect of estrogen hormones.

The Head to Head trial: Letrozole vs anastrozole as adjuvant treatment of postmenopausal patients with node positive breast cancer

10672 Introduction: Aromatase Inhibitors (AIs) have demonstrated both efficacy and safety advantages over tamoxifen (T) in all treatment settings in breast cancer (BC) and are becoming the new standard of care as endocrine therapy for postmenopausal patients (PM) with BC. Rationale: Cumulative evidence suggests that all AIs may not be the same, raising the question of whether there is a superior AI, and whether any specific patient populations derive differing degrees of benefit from a particular AI. In the ATAC trial, evaluating anastrozole (A) in PM patients with early breast cancer (EBC), at 33 months median follow up the risk of recurrence in the hormone receptor positive (HR+) population was reduced by 22%.The BIG 1–98 Trial, evaluating letrozole (L) in PM women with EBC, showed a significant benefit in favor of L over T at a median follow up of 26 months, with a 19% reduction in the risk of recurrence; in subgroup analyses, L significantly decreased the risk of recurrence in LN+ patients and in patients who received adjuvant chemotherapy. This study is a head to head comparison of L and A in HR+, LN+ PM patients with EBC and aims to compare L vs A in the adjuvant treatment of these patients. Design and Methods: This is a Phase IIIb open-label, randomized, multicentre study including 4000 PM patients from up to 250 international sites. PM patients with HR+, LN+ BC who have recently undergone surgery for primary BC will be randomized to either receive L 2.5 mg or A 1 mg daily. Treatment will commence following completion of standard chemotherapy (if given) and concurrently with radiotherapy (if given)Patients will receive treatment until disease recurrence/relapse for up to 5 years. Patients will be stratified by number of LN and HER2 status. The primary objective is disease free survival at 5 years for L and A. Secondary objectives include safety, overall survival, time to distant metastases and time to contralateral breast cancer. Data analysis will be conducted by an independent group of investigators. Summary: Updated patient accrual figures, including any available early safety data, will be presented at the meeting. No significant financial relationships to disclose.

Exemestane (E) vs tamoxifen (T) as neoadjuvant endocrine therapy for postmenopausal women with ER+ breast cancer (T2N1–2, T3N0–1, T4N0M0)

530 Background: There is considerable evidence that aromatase inhibitors are superior to T as first line endocrine therapy for metastatic disease. E an aromatase inactivator, is effective in women whose tumor has progressed despite T therapy. Methods: 151 PM women with ER+ breast cancer (BC) were randomly assigned once-daily treatment with either E alone 25 mg (n=76), or T alone (n=75) for 3 months. The primary endpoint was clinical objective response (OR). Secondary endpoints were OR determined by mammography and ultrasound, and number of pts who underwent breast conserving surgery (BCS). Result: Clinical, mammography, BCS rate are shown in the table. A pathological CR was shown in two pts in the E group and 2 pts in the T group. Response to any type of endocrine treatment was more likely in pts with higher levels of ER expression. Median time to response was 57 days in the E group and 70 days in the T group (p<0.05). All pts with disease progression after endocrine treatment were recommended to receive chemotherapy AT (doxorubicine 60 mg/m2 + paclitaxel 200 mg/m2, every 3 weeks to 4 cycles). Clinical OR after chemotherapy (second line neoadjuvant treatment) was 59.6%. During 50 months of follow up local recurrences were detected in 5.2% pts of E group and 8% pts in T group (p>0.05). 3-year disease free survival rates were 78.9% in E group and 74.6% in T group (p>0.05). Conclusion: E is more effective than T as neoadjuvant therapy for PM pts with ER+ tumors in rate of clinical OR and BCS. No significant financial relationships to disclose.

Modulation of Metoprolol Pharmacokinetics and Hemodynamics by Diphenhydramine Coadministration during Exercise Testing in Healthy Premenopausal Women

Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC(50) value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC(50) value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen.

The effect of exemestane on the lipidemic profile of breast cancer patients: Preliminary results of the TEAM trial Greek sub-study

799 Background: Side effects of endocrine therapy for breast cancer (BC) may have clinical implications. Drugs that alter lipid profile potentially interfere with the risk of developing cardiovascular disease (CVD). Tamoxifen (T) has proven to have a favorable effect on CVD risk factors by modestly decreasing total plasma cholesterol (TC) and low-density lipoprotein (LDL) levels while having little effect on high-density lipoprotein (HDL). However, it increases serum triglycerides (TG). Exemestane (Ε), a steroidal anti-aromatase agent with demonstrated efficacy in (PM) metastatic BC patients, is under evaluation in the adjuvant setting but, there is limited information about its effect on lipidemic parameters. Methods: TEAM -Tamoxifen and Exemestane Adjuvant Multicenter–international trial is a direct comparison of 5 yrs of T to 5 yrs of E in PM women with ER+, BC and in the Greek substudy effect of either treatment on lipids is studied in comparison to pretreatment values. Data on TC, HDL, LDL and TG levels at 3 and 6 months of treatment have been analyzed in 56 patients. Multiple comparisons of the mean value of each parameter at different time points (baseline, 3 and 6 months) were performed for each arm of the trial. Results: After 6 months treatment, comparison of percentage changes of TC and HDL levels from baseline values between groups is non significant. There is a trend to increased LDL levels in E arm (+8.97% and + 5.72% at 3 and 6 months, respectively) and decreased levels (- 0.01% and - 15.24% at 3 and 6 months) in T arm, however, the changes from baseline values between groups are NS. TG levels are increased at month 3 (+18.81%) and remained elevated (+8.62%) at month 6 in patients on T, while in patients on E it progressively decreased at both time points (-4.84% and -7.18%), with differences being significant at month 3 (p=0,037).Conclusions: From the currently available preliminary data E appears to have a stabilizing effect on TC and HDL parallel to the beneficial effect of T. Exemestane treatment results in a mild but non-significant increase in LDL levels at 3 and 6 months and a beneficial effect on TG levels. Data continues to mature. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacia; Shering Plough Pfizer-Pharmacia

The effect of exemestane on the lipidemic profile of breast cancer patients: Preliminary results of the TEAM trial Greek sub-study

799 Background: Side effects of endocrine therapy for breast cancer (BC) may have clinical implications. Drugs that alter lipid profile potentially interfere with the risk of developing cardiovascular disease (CVD). Tamoxifen (T) has proven to have a favorable effect on CVD risk factors by modestly decreasing total plasma cholesterol (TC) and low-density lipoprotein (LDL) levels while having little effect on high-density lipoprotein (HDL). However, it increases serum triglycerides (TG). Exemestane (Ε), a steroidal anti-aromatase agent with demonstrated efficacy in (PM) metastatic BC patients, is under evaluation in the adjuvant setting but, there is limited information about its effect on lipidemic parameters. Methods: TEAM -Tamoxifen and Exemestane Adjuvant Multicenter–international trial is a direct comparison of 5 yrs of T to 5 yrs of E in PM women with ER+, BC and in the Greek substudy effect of either treatment on lipids is studied in comparison to pretreatment values. Data on TC, HDL, LDL and TG levels at 3 and 6 months of treatment have been analyzed in 56 patients. Multiple comparisons of the mean value of each parameter at different time points (baseline, 3 and 6 months) were performed for each arm of the trial. Results: After 6 months treatment, comparison of percentage changes of TC and HDL levels from baseline values between groups is non significant. There is a trend to increased LDL levels in E arm (+8.97% and + 5.72% at 3 and 6 months, respectively) and decreased levels (- 0.01% and - 15.24% at 3 and 6 months) in T arm, however, the changes from baseline values between groups are NS. TG levels are increased at month 3 (+18.81%) and remained elevated (+8.62%) at month 6 in patients on T, while in patients on E it progressively decreased at both time points (-4.84% and -7.18%), with differences being significant at month 3 (p=0,037).Conclusions: From the currently available preliminary data E appears to have a stabilizing effect on TC and HDL parallel to the beneficial effect of T. Exemestane treatment results in a mild but non-significant increase in LDL levels at 3 and 6 months and a beneficial effect on TG levels. Data continues to mature. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacia; Shering Plough Pfizer-Pharmacia