PreM Women Research Articles

Differences in the Presentation and Outcome between Premenopausal and Postmenopausal Primary Hyperparathyroidism Indian Women: A Single-Center Experience.

Primary hyperparathyroidism (PHPT) is an endocrine disorder wherein enlargement of one or more of the parathyroid glands causes autonomous overproduction of the parathyroid hormone (PTH), which leads to high serum calcium levels. The objective of this study was to compare the clinical, laboratory, and operative variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT. A retrospective analysis of the data of female patients who underwent surgery for PHPT at a single center, from January 2011 to December 2020, was done. Patients with familial PHPT and secondary hyperparathyroidism were not included. Of the 130 women with PHPT, 44.6% were pre-M and 55.4% were post-M. A significantly higher number of pre-M females were symptomatic compared to post-M females (pre-M vs. post-M, 84.5% vs. 68.1%, P = 0.031). Renal calculi were more common in pre-M women (34.5% vs. 18.1%, P = 0.032), while the rest of the clinical features were comparable between the two groups. The proportion of women with osteoporosis (6.7% vs. 19.4%, P = 0.071), hypertension (13.8% vs. 34.7%, P = 0.012), and diabetes mellitus (3.5% vs. 16.7%, P = 0.033) was lesser in the pre-M group. Elevated serum alkaline phosphatase levels were significantly more prevalent in the pre-M group (37.9% vs. 20.8%, P = 0.032). The mean serum calcium (12.35 ± 1.28 vs. 11.96 ± 1.22 mg/dL, P = 0.079), median serum PTH (334 vs. 239 pg/mL, P = 0.051), and median weight of the operated adenomas (1.75 vs. 1.45 g, P = 0.075) were also higher in pre-M females. The proportion of ectopic adenomas and multiple adenomas, presurgery adenoma localization rates, and disease cure rates did not differ according to the menopausal status. The occurrence of postoperative hungry bone syndrome was higher in the pre-M women (15.5% vs. 1.4%, P = 0.008). The majority of women with PHPT are post-M, but symptomatic presentation is more common in pre-M females. The severity of the disease appears to be more in pre-M women; however, imaging and operative variables generally did not significantly differ between the two groups.

Differences in Primary Hyperparathyroidism Between Pre- and Postmenopausal Women in India

ObjectivePrimary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becomes more prevalent after menopause. In this study, we compared the demographic, clinical, and biochemical variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT. MethodsA retrospective analysis (from 2005 to 2019) of enrolled women PHPT patients from an online Indian PHPT registry. ResultsOf the women with PHPT, 232 and 122 were pre-M and post-M, respectively. The number of post-M PHPT cases registered had a 3.3-fold increase in 2015-2019 from 2005-2009 compared with only a 2.5-fold increase in pre-M cases in the same duration. The majority were symptomatic (90%), although pre-M had a higher proportion of symptomatic than post-M (92% vs 85%; P = .04). Pre-M women showed more prevalence of osteitis fibrosa cystica than post-M women (28% vs 13%; P = .03), although hypertension and gallstone disease were seen more frequently in post-M PHPT women. Pre-M women had a significantly higher median PTH (403 vs 246 pg/mL; P = .02) and median alkaline phosphatase (202 vs 145 pg/mL; P = .02) than post-M women, and vitamin D deficiency was more common in pre-M women (58% vs 45%; P = .03). Gland localization, tumor weight, and disease cure rates did not differ according to menopausal status. ConclusionPHPT was more prevalent in pre-M women, although the number of post-M cases had significantly increased in the last 10 years. Pre-M women had generally more severe clinical and biochemical variables than post-M PHPT women.

Abstract P246: Sex Differences In The Association Between Soluble Prorenin Receptor And Physiological And Cardiometabolic Risk Factors In Healthy Humans Varying In Age And Obesity

The prorenin receptor (PRR), which regulates renin-angiotensin system in multiple tissues, can be cleaved to generate soluble PRR (sPRR) in plasma. sPRR concentrations vary with clinical conditions such as metabolic syndrome, pregnancy, chronic kidney disease and heart failure in humans. However, whether sPRR is associated with aging and healthy obesity in men and women is unknown. We aimed to evaluate if there are sex-specific associations of sPRR with cardiometabolic risk factors among healthy women and men varying in age and obesity. Circulating cardiometabolic, vascular and inflammatory risk factors and sPRR (via ELISA) were measured in unmedicated healthy men (n=55; age 39 ± 16 yrs; BMI 29 ± 4 kg/m2) and women (n=34; age 44 ± 16 yrs; BMI 30 ± 7 kg/m2) at the University of Iowa. Women were classified by menopausal status [pre-menopausal, pre-M (n=18) and post-menopausal, post-M (n=16)]. Independent t -test was used to compare means and pearson correlation was examined. In men, sPRR was not related to age, systolic blood pressure (SBP), BMI, cholesterol or endothelial function (brachial artery flow mediated dilation, FMD), but was correlated with plasma TNFα (r=0.50, P<0.05). sPRR was higher in overweight/obese (BMI ≥ 25 kg/m2) compared with non-obese men (n=48; 10.8 ± 0.4 vs. n=7; 8.3 ± 0.4 ng/ml, P<0.05). In women, sPRR did not correlate with BMI or SBP, but correlated with total cholesterol (r=0.49, P<0.05) and TNFα (r=0.49, P<0.05). sPRR correlated with age in women with a BMI<30 (r=0.54, P<0.05) but not a BMI ≥30 kg/m2. sPRR was significantly higher in post-M compared with Pre-M women independent of obesity or hypertension status (12.1 ± 0.5 vs. 10.1 ± 0.4 ng/ml, P<0.05). sPRR correlated with FMD only in obese women (%FMD: r=-0.50, P<0.05), indicating a relation of sPRR with endothelial dysfunction in obese women. Interestingly, sPRR was significantly higher in Pre-M compared with non-obese men and menopause further exacerbated the difference. In conclusion, sPRR is associated with TNFα in both men and women, but there are sex differences in the relation with BMI, age, cholesterol and endothelial function in humans. sPRR concentrations were higher in post-M compared with pre-M women, suggesting that PRR could contribute to cardiovascular risk in post-M women.

Abstract 121: Mammary adipocytes drive breast tumor progression and angiogenesis via the VEGF/IL6/STAT3 signaling axis

Abstract Obesity is associated with a substantially increased risk (~50%) and a poor prognosis of breast cancer (BC) in postmenopausal (PM) women. The mechanism(s) underlying obesity-related BC are not clearly understood and, to date, most studies focus on the systemic effects of subcutaneous or visceral adipocytes on BC. We hypothesize that the increased local presence of ‘obese' mammary adipocytes within the breast microenvironment promotes the acquisition of an angiogenic and invasive breast tumor cell phenotype and thereby markedly accelerates tumor proliferation and progression. We first asked whether local interactions between mammary adipocytes and BC cells might promote tumor growth and if so, what the underlying mechanism(s) might be. Preadipocytes isolated from mammary adipose tissues of overweight/obese pre- (Pre-M; n=7) and post-menopausal (PM; n=9) women were differentiated into mature adipocytes using standard protocols. The effects of both normal (NA) and cancer-associated (CAA) mammary adipocyte secretome from Pre-M and PM obese women were tested on human and mouse BC cell lines respectively. BC cells (MDA-MB-436, MCF-7, M-Wnt), when treated with the secretome of mammary adipocytes from obese women (ObAd-CM), upregulated potent angiogenic factors, including VEGF-A, Angiopoietin-1, Jagged 1, HIF1-α and bFGF and significantly suppressed the angiogenesis inhibitor Tsp-1. ObAd-CM from both Pre-M and PM women significantly stimulated BC cell proliferation, migration and invasion. Importantly, compared to Pre-M patients, CAA Ad-CM from PM patients promoted higher levels of BC cell proliferation, migration and invasion. Pre-treatment with ObAd-CM resulted in increased endothelial cell (EC) recruitment by BC cells, an indispensable step in tumor angiogenesis. This effect was reversed by VEGF neutralization. In addition, ObAd-CM treatment significantly increased EC proliferation and capillary tube formation. Adipokines such as IL-6, IL-8, MCP-1, adiponectin and leptin were highly expressed in ObAd-CM. Of these, IL-6 neutralization alone inhibited the ObAd-CM-induced migratory and invasive phenotype of BC cells. Treatment with ObAd-CM also resulted in significant activation of pSTAT3, pAkt and pErk in BC cells. STAT3 inhibition reversed the ObAd-CM-mediated effects on BC cell proliferation and migration, suggesting that the pro-tumorigenic effects of Ob mammary adipocytes are mediated via IL-6/STAT3 signaling. Taken together, our results indicate that Ob mammary adipocytes promote migration, proliferation, invasion and the angiogenic phenotype in BC cells and suggest that targeting the VEGF/IL-6/STAT3 signaling axis may be a useful strategy in obesity-driven breast tumor growth and metastasis. [Supported by NIH RO1CA185530, the Karp Family Foundation and the Breast Cancer Research Foundation] Citation Format: Roopali Roy, Takaya Shimura, Lauren Merritt, Katherine Gonzalez, Emily Man, Margaret Lotz-Bousvaros, Susan Pories, Marsha A. Moses. Mammary adipocytes drive breast tumor progression and angiogenesis via the VEGF/IL6/STAT3 signaling axis [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 121.

Abstract OT2-02-03: NSABP FB-13: An assessment of the biological and clinical effects of palbociclib with ovarian suppression and letrozole in the neoadjuvant treatment of pts (pts) with premenopausal (preM) estrogen-receptor positive/HER2-negative primary breast cancer

Abstract Background: There have been few studies of neoadjuvant endocrine therapy in premenopausal (preM) women despite low pathologic complete response (pCR) rates using neoadjuvant chemotherapy in ER+/HER2− pts. Suppression of Ki67, particularly complete cell cycle arrest (CCCA) defined as Ki67 <2.7% after 2 wks of neoadjuvant endocrine therapy has been demonstrated to correlate with recurrence-free survival. PALLET, a randomized, neoadjuvant endocrine trial evaluated letrozole (AI) v palbociclib (pal) in combination with AI for 14 wks in post-menopausal women. This study demonstrated a modest improvement in clinical response (54.3% with the combination v 49.5% with AI alone) but showed a significant difference in achievement of CCCA (Ki67<2.7%) with the combination of pal and AI v AI alone (90% v 59%). We seek to evaluate this combination, given over a longer duration in the neoadjuvant setting, in preM women with early-stage breast cancer. Trial design: FB-13 is a phase II, open-label study to examine the biological and clinical effect of neoadjuvant endocrine therapy with AI, pal, and ovarian suppression in preM pts with ER+, HER2-negative early invasive breast cancer. 76 pts will be stratified into one of two approximately equal sized cohorts based on Oncotype DX Breast Recurrence Score (RS) (cohort 1: pts with RS <11 or cohort 2: pts with RS 11 to <26). A baseline tumor biopsy prior to start of therapy (tx) for RS and Ki67 will both be centrally determined. Pts in both cohorts will receive letrozole 2.5 mg by mouth daily, pal 125 mg by mouth daily for 21 days of a 28-day cycle, and goserelin 3.6 mg SQ injection every 28 days. At wk 6, pts will have core-cut biopsies for real-time evaluation of Ki67. Pts from both cohorts who have Ki67 <10% will continue tx for a total of 6 cycles. Pts with a persistent Ki67 ≥10% will permanently discontinue tx and begin neoadjuvant chemotherapy or proceed to surgery at physician discretion. Eligibility: FB-13 is enrolling preM women newly diagnosed with ER+/HER2− early breast cancer who are candidates for neoadjuvant endocrine therapy. Pts must be preM based on standard definitions. Primary tumor size must be >2 cm. RS must be <26. Mandatory pre-treatment and post-surgical samples will be collected and analyzed for RS and Ki67, as well as additional biomarkers to correlate with response. Blood will be collected at baseline, 4 wks, and at 24 wks for estradiol levels to demonstrate ovarian suppression. A 4-wk estradiol level in the postmenopausal range will be required to receive further treatment. Specific aims: The primary aim is to determine complete cell cycle arrest as indicated by a Ki67 <2.7% at 6 wks. Secondary aims are to determine overall response rate (ORR) by clinical exam and ultrasound, the pCR, to generate a Preoperative Endocrine Prognostic Index (PEPI score), to compare the change in Ki67 at baseline, after 6 wks and 24 wks, and to determine the rate of breast-conservation therapy. Statistical methods: We anticipate that the addition of palbociclib to ovarian suppression and AI will result in a measurable drop in Ki67 and a high ORR. The null hypothesis is ORR <40% and alternative hypothesis is ORR >60%. We anticipate that >60% of pts in each cohort will have 6 wk Ki67 <2.7% and clinical response >35%. Present accrual and target accrual: Currently 12 of a planned 76 pts have been enrolled. NSABP Operations contact information: Diana Gosik, Diana.Gosik@nsabp.org NCT03628066 SUPPORT: Genomic Health Inc, Pfizer, NSABP Foundation Citation Format: Shannon Puhalla, Greg Yothers, Amy P Sing, Thomas B Julian, Norman Wolmark, Samuel A Jacobs. NSABP FB-13: An assessment of the biological and clinical effects of palbociclib with ovarian suppression and letrozole in the neoadjuvant treatment of pts (pts) with premenopausal (preM) estrogen-receptor positive/HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-03.

Effects of ‎tamoxifen on the reproductive system of female breast cancer patients: an ultrasound-based cohort study

Background: Tamoxifen (TMX) is regarded as standard treatment for breast cancer (BC) patients‎. In recent years, several studies have reported gynecological side effects and due to TMX's estrogenic effects. Here, we evaluate the side effects of TMX on the ‎endometrium and ovaries of female BC patients. Methods: This was an ultrasound-based cohort study conducted in three oncology centers in Baghdad, Iraq. A total of ‎‎255 female patients were included, 140 premenopausal (PreM) and 115 postmenopausal (PostM), with estrogen receptor (ER)-positive BC using TMX adjuvant hormonal treatment for at least three months after surgery and adjuvant ‎chemo/radiotherapy.‎ Ultrasound (US) on the endometrium and ovaries of the women following ‎BC surgery/chemotherapy (baseline) and at 3, 6, 12, and 24 months following was performed‎. Data collected included age, menopausal status, co-morbid chronic illness and medications, including duration of TMX treatment. Results: Presence of ovarian cyst was significantly higher in the PreM ‎compared to PostM ‎women, while there were no significant differences for other gynecological findings.‎ At ‎baseline, endometrial thickness (ET) was significantly higher in the PreM compared to the PostM women. In both groups, women with increased ET became more frequent from baseline to 3 ‎months, from 3 to 6 ‎months, from 6 to 12 months, and from 12 ‎ to 24 months. At all time periods, ‎women with increased ET was ‎significantly higher in the PostM compared PreM women, resulting ‎in a risk of ET increase by 6 folds (ranging from 3 – ‎‎11 folds) ‎in PostM compared to PreM women. Conclusions: Longer duration of TMX is associated with increased ET. Duration of TMX did not appear to increase the risk of various gynecological outcomes, for example endometrial cancer rate was low. Finally, there was an increase in ET, which appeared to be six-folds higher in PostM compared to PreM women.‎

EP31.08: Does hormonal status influence uterine venous diameter?

Pelvic venous congestion (PVC) primarily affects premenopausal (Pre-M) women and is characterised by evidence of pelvic varicosities on transvaginal ultrasound (TVS). Postmenopausal (Po-M) women rarely exhibit these symptoms suggesting that hormonal influence is a definite factor. The aim of this study was to examine the affect hormonal status has on vein diameter. This was a single-centre, prospective cross-sectional study of women attending our general gynecology clinic during a 16-month period. Demographic data and a full medical/surgical history were recorded. Exclusion criteria included age<18 years, previous hysterectomy, contraindication to/declining TVS and evidence of pelvic pathology on TVS. All women underwent TVS assessment of the pelvic organs and pelvic veins. The Mann Whitney U-test was used to compare the diameters between Pre-M and Po-M women. Linear regression was performed to examine whether exogenous hormone use influenced venous diameter. 486 women had normal pelvic organs out of 1500 women examined. Of these, 375 were Pre-M and 111 were Po-M. Overall, the pelvic vessel diameters were smaller in Po-M women, with statistical significance observed in the right vein and both sides combined. Exogenous hormone use in the Pre-M group was associated with smaller vessel diameters, with statistical significance in the left vein (p = 0.001). There was no association between vein diameter and HRT use in the Po-M group (p = 0.98 left vein; p = 0.64 right vein). Our findings showed that Pre-M women have larger pelvic veins than Po-M women. These findings provide further insight into the biomechanics of veins and hence suggest that they are sensitive to hormonal fluctuations. This is further supported by our findings revealing that suppression of ovarian activity with hormones in Pre-M women leads to a reduction in vein diameter, which is often treatment for PVC. EP31.08: Table 1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The influence of the expression of steroid receptors on angiogenesis, proliferation and apoptosis in myomas of pre- and postmenopausal women

Introduction/Objective. The aim of this study was to determine the effects of the estrogen and progesterone receptor status on angiogenesis, proliferation, and apoptosis of myoma cells in premenopausal (PreM) and postmenopausal (PostM) women. Methods. This was a cross section; clinical-experimental, retrospective, non-interventional study in the field of the study of fundamental pathogenesis mechanisms of disease using pathohistological materials from the existing archive. The research included 76 patients diagnosed with uterine leiomyomas, operatively treated in the Clinic for Gynecology and Obstetrics, Clinical Centre Kragujevac, Serbia. According to the menstrual status, we formed two experimental subgroups. The first group was PreM women (n = 35; 46.2 ? 5.02 years old), and the second group was PostM women (n = 41; 60.25 ? 5.41 years old). Hematoxylin-eosin staining for myoma and myometrium was conducted, as well as immunohistochemistry for ER?, ER?, PR?, vascular endothelial growth factor, endoglin, Ki67, and caspase-3. Results. Progesterone receptor was overexpressed in myoma and myometrium of PreM compared to myoma and myometrium of PostM women. Expression of caspase-3 was a statistically significant increase in PostM women compared to PreM group. ER? and ER? were not changed among groups neither in myoma nor in myometrium samples. Conclusion. According to our data, PR? had higher influence on apoptosis and cell growth than estrogen receptors. Since PR? was increased in PreM in both myoma and myometrium, probably this expression led further to lower expression of apoptotic marker in PreM women.

Menopausal Status and Outcomes of BRCA Mutation Carriers with Breast Cancer

Outcomes based on menopausal status of breast cancer (BC) patients who are BRCA mutations carriers (BRCAm) are not well known. A prospective database identified 88 BRCAm with BC from 2005 to 2015. Of the 88 patients, 68 (77.3%) women were premenopausal (Pre-M) and 20 (22.7%) were postmenopausal (Post-M). In the Pre-M group, 52.9 per cent of patients had triple-negative (TN) BC, whereas in the Post-M group, there were more estrogen receptor +(65%; P = 0.129) and less TN (25%; P = 0.041) tumors. Median tumor size was significantly larger in the Pre-M group compared with the Post-M group (P <0.001). Pre-M women were more likely to present with stage III cancers (14.7% vs 0%, respectively, P = 0.082). Ten-year overall survival was 87.9 per cent in the Pre-M group and 93.8 per cent in the Post-M group (P = 0.44), and 25.3 per cent of Pre-M women had recurrences compared with 11.5 per cent of Post-M women (P = 0.24). Premenopausal BRCAm with BC are more likely to have TN, higher stage disease, and twice the number of recurrences at 10 years than Post-M BRCAm. Our study is the first to show worse BC outcomes for Pre-M BRCAm compared with Post-M BRCAm women.

Sex differences in tolerability to Anti-PD1 therapy: Are we all equal?

9547 Background: Immune related adverse events (IRAEs) have emerged as a serious clinical problem in the use of immune checkpoint inhibitors. The etiology and risk factors for these potentially life-threatening adverse events remain unknown. Therefore, we assessed sex differences in tolerability to anti-PD1 therapy. Methods: All patients (pts) with metastatic melanoma treated with anti-PD1 therapy at Mayo Clinic Rochester from 2014 to 2017 were reviewed. Ocular melanoma cases were excluded. Kaplan-Meier method was used for time-to-event analysis. Results: 245 pts were identified, 148 (60%) were men, 30 (12%) were premenopausal (Pre-M) (≤52 years) and 67 (27%) were postmenopausal (Post-M) women. Baseline characteristics were similar among groups (Table 1). Pre-M women were more likely to experience IRAEs compared to Post-M women and men (67% vs. 60% vs. 46%, p < 0.04). In 23% of Pre-M women anti-PD1 therapy was discontinued due to irAE (men 12%). Pre-M women were more likely to experience endocrinopathies (35% vs. 10%, p < 0.02) and cutaneous reactions (25% vs. 15%, p < 0.02) compared to men. All cases of diabetic ketoacidosis were observed in Pre-M women (n = 6). No differences in grade ≥3 toxicities were seen across groups. Pts with IRAEs were more likely to have a radiographic response to anti-PD1 therapy regardless of sex (68% vs. 44%, p < 0.002). There was a trend towards better PFS in men with IRAEs compared to men without IRAEs (16.5 months vs. 9.7 months, p < 0.05). Conclusions: Pre-M Women were more likely to experience IRAEs compared to Post-M women and men. An association between IRAEs and response to therapy was also observed. Larger studies are needed to confirm these results and investigate etiologic mechanisms underlying these associations. Characteristics Pre-M % (n) Post-M % (n) Men % (n) p value Liver metastasis 33 (10) 33 (22) 30 (45) 0.91 Lung metastasis 47 (14) 30 (20) 42 (62) 0.16 Prior GM-CSF 43 (13) 27 (18) 18 (27) 0.01 Prior radiation 37 (11) 54 (36) 59 (87) 0.08 Prior chemotherapy 13 (4) 16 (11) 18 (27) 0.79 IRAEs 67 (20) 60 (40) 46 (68) 0.04 ≥3 grade IRAEs 50 (10) 43 (17) 31 (21) 0.12 Discontinuation of anti-PD1 due to toxicity 23 (7) 15 (10) 12 (18) 0.37

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&amp;lt;0.0001) and multivariate regression analysis (P&amp;lt;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&amp;lt;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.

Palbociclib (PAL) in combination with fulvestrant (F) in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy – results from Paloma-3.

524Background: Standard endocrine therapy options for PreM women with MBC are limited and better options are needed. PALOMA-3 is the first large registrational study to include PreM women with HR+ ...

Abstract LB-193: Prediagnostic breast cancer metabolites in Mexican Americans: a nested case control study

Abstract Breast cancer (BrCa) is the most common invasive cancer in Hispanic women. Although at decreased risk, Hispanic women are diagnosed at younger ages and with more aggressive disease than non-Hispanic Whites. Early detection is key in BrCa survival; however, there are no pre-diagnostic circulating biomarkers for early detection. This pilot nested case-control study based on our Mexican-American Cohort (MAC) study evaluates the role of global metabolic expression in predicting BrCa risk. MAC includes ∼23,000 participants in the Houston area with baseline blood specimens and epidemiological data. Using mass spectrometry-based global protein expression, 435 plasma metabolites were analyzed by Metabolon in 30 invasive BrCa cases (14 pre- (preM) and 16 post-menopausal (postM)) diagnosed 1-5 years after enrollment and 40 healthy controls (matched to cases on age, menopausal status) and length of follow-up). Mean age of preM women was 37.6 years (range 32-43) compared to 63.4 for postM (range 50-81). Using principal component analysis, we evaluated differences by disease and menopausal status. We found 76 metabolites that differed significantly (P&amp;lt;0.05) between cases and controls among postM women compared to only 13 metabolites in preM women. Using a pathway-based approach, we found that the majority of case-control differences were in metabolites related to hormone, lipid and energy metabolism. The specific metabolites differed by menopausal status. In postM cases, levels of steroid hormones epiandrosterone sulfate, androsterone sulfate, and 5-alpha-androstan-3beta,17beta-diol disulfate were higher than in controls; among preM cases, steroid hormones 5-alpha-pregnan-3beta,20alpha-diol disulfate and 5-alpha-pregnan-3alpha,20beta-diol disulfate 1 levels were higher. PostM cases had significantly (P&amp;lt;0.05) lower levels in fatty acids valerylcarnitine and butyrylcarnitine and higher levels of monoacylglycerols and glycerol 3-phosphate (G3P) than controls; there were no significant differences in these metabolites in preM cases and controls. The statistically significant (P&amp;lt;0.05) decreases in 3-phosphoglycerate, pyruvate, sarcosine (N-methylglycine), citrate, and malate which are all associated with glycolysis and the tricarboxylic acid cycle found in cases compared to controls irrespective of menopausal status, suggest energy metabolism may be associated with BrCa risk. In summary, our findings suggest: (1) case-control differences in plasma levels of specific metabolites associated with key functional pathways; (2) the specific metabolites and number of relevant metabolites differs by menopausal status; and (3) these differences are detectable years prior to diagnosis. Future studies exploring these associations with tumor hormone receptor status, dietary intake and anthropometric measurements will aid in further identifying key pre-diagnostic plasma markers for BrCa. Citation Format: Sara S. Strom, Hua Zhao, Abenaa Brewster, Yuko Yamamura. Prediagnostic breast cancer metabolites in Mexican Americans: a nested case control study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-193. doi:10.1158/1538-7445.AM2015-LB-193

PP.24.06

Objective:The prevalence of the risk of CVD and hypertension in women increases when they reach menopause. The aim of this study was to assess the prevalence and risk factors of hypertension in pre-menopausal (Pre-M) women and post-menopausal (Post-M) women and determine whether years since menopaus

Oral health in postmenopausal and premenopausal women after myocardial infarction in Poland: a preliminary study.

IntroductionAge and hormonal disorders are recognized factors impacting the periodontium and the prevalence of cardiovascular diseases, but as yet the relationship between these two conditions in postmenopausal (post-M) and premenopausal (pre-M) women in Poland has not been assessed. The aim of this study was to compare the periodontal status in women after myocardial infarction (MI) with women without MI history and to determine risk factors for periodontitis.Material and methodsThe study included 35 women hospitalized due to MI, average age 54.7 ± 9.4 years, and 96 women randomly drawn from the general population, average age 56.1 ± 10.0 years. All women were checked for periodontitis risk factors (education, socioeconomic status, tobacco smoking, stress), and underwent dental examination.ResultsThe lowest number of teeth was found in post-M women after MI (median = 8), whereas pre-M women without MI history had 25 teeth. Edentulousness occurred more frequently in post-M women compared with pre-M women (12.2% vs. 0%), the same was observed for advanced periodontitis (28.4% vs. 21.1%). The severity of periodontitis was highest in the post-M subgroup (more than half demonstrated advanced periodontitis or edentulousness). The most important risk factor for periodontitis, regardless of age, was the level of education. In post-M women the second risk factor was smoking, while in pre-M women negative stress.ConclusionsThe status of oral health in post-M women is unsatisfactory, particularly in those affected by cardiovascular diseases. It is necessary to take preventive and educational measures targeted at these women.

Abstract P4-05-03: Unique genetic, epigenetic, and transcriptomic changes in premenopausal breast cancer suggest novel strategies for therapy

Abstract Breast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM) even when controlling for prognostic variables. In particular, preM ER+ tumors have a poor prognosis on endocrine therapy. There is, however, a paucity of studies characterizing molecular alterations in premenopausal tumors, a potential avenue for finding personalized therapies for this group of women. We analyzed gene expression, CNV, methylation, and somatic mutations in tumors from preM (≤45; ER+ n = 110, and ER- n = 39) and postM (≥55, ER+ n = 392, and ER- n = 102) women in The Cancer Genome Atlas (TCGA). Unbiased hierarchical clustering of 2,900 most variably expressed genes (using both RNA-seq and Agilent expression array data) in the whole dataset (n = 643) identified four major subtypes which correlated highly with the PAM50 defined subtypes LumA, LumB, Basal and HER2; however, there wasn't any separation between preM and postM samples. Similarly, principal component analysis using 10,000 genes with the highest inter-quartile range (IQR) demonstrated high similarity across preM and postM samples. Direct examination of gene expression differences between PreM and PostM ER+ tumors using unpaired t-test (5% FDR) identified 3,044 differentially expressed genes. The genes most upregulated in premenopausal tumors included AREG, TFPI2, MSMB, TCN1, and GLRA3. Ingenuity Pathway Analysis revealed a highly significant enrichment for TGFb (p&amp;lt;1.9E-16) pathway activity in preM tumors. Intriguingly, no significant gene expression differences between preM and postM ER- tumors were identified. We thus then focused on genetic and epigenetic alterations that may underlie these transcriptomic changes in ER+ preM tumors. Comparison of methylation (450K Illumina array) between preM and postM ER+ tumors showed a difference in 1% (n = 1,738) of the probes. Genes with the largest difference included ESR1, SIM2, and KLF6. Significant differences in DNA copy number variation (Affymetrix SNP 6.0 array) were also identified in ER+ preM tumors. A number of somatic mutations were significantly enriched in preM ER+ tumors including DSPP and GATA3. Integrated analysis also showed that approximately half of the observed differences in gene expression are driven by CNVs. Conclusion: Our in silico study has identified a number of genes and pathways which are significantly altered between preM and postM ER+ breast cancer. Distinct genetic and epigenetic differences suggest unique etiology for some preM tumors. Currently ongoing Paradigm analysis, and confirmatory studies using METABRIC data are expected to further identify pathways that could specifically be targeted in premenopausal breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-03.

Obstructive Sleep Apnea Severity Is Associated with Left Ventricular Mass Independent of Other Cardiovascular Risk Factors in Morbid Obesity

To evaluate the relation between obstructive sleep apnea (OSA) and left ventricular mass (LVM) in morbid obesity and the influence of gender, menopausal status, anthropometry, body composition, hypertension, and other cardiovascular risk factors in this relationship. Cross-sectional descriptive study. Polysomnographic and echocardiographic studies were performed in a cohort of 242 patients (86 men, 100 premenopausal (PreM) and 56 postmenopausal (PostM) women), with grade II obesity and above (BMI: 43.7 ± 0.4 kg/m(2)) to investigate OSA and LVM respectively. Anthropometry, body composition, glucose tolerance, and blood pressure were also recorded. OSA to different degrees was diagnosed in 76.2% of the patients (n: 166), its prevalence being 90.9% (n: 70) for men, and 76% (n: 38) and 63.8% (n: 58) for PostM and PreM women, respectively (p < 0.01). LVM excess was greatest for PostM women (90.2%), followed by men (81.9%) and PreM females (69.6%) (p < 0.01). LVM values increased in accordance to OSA severity (absence, 193.7 ± 6.9 g; mild, 192.6 ± 7.8 g; moderate, 240.5 ± 12.5 g; severe, 273.6 ± 14.6 g; p < 0.01). LVM magnitude correlated with the menopausal state, age, central adiposity, hypertension (HT), type 2 diabetes (DM), desaturation index (DI), and apnea-hypopnea index (AHI) (r = 0.41; p < 0.01). The relationship between LVM and AHI persisted in the multivariate analysis (β = 0.25; p < 0.05) after adjusting for age, gender, menopausal state, BMI, waist circumference, neck circumference, DI, fasting plasma glucose, DM, and HT. But if tobacco habits are included, the statistical difference disappears (β = 0.22; p = 0.06). Morbid obesity is frequently associated with abnormal LVM, particularly in patients with OSA; this association is independent of HT, BMI, body composition, and other clinical factors, supporting a direct role of OSA on LVM in morbid obesity. This suggests that OSA and LVM might be taken as predictors of the cardiovascular risk in these patients.

Age determines longitudinal changes in body composition better than menopausal and bone status: The OFELY study

Long-term body composition (BC) changes and their determinants have been rarely explored. We aimed to evaluate BC changes in French women from the Os des Femmes de Lyon (OFELY) cohort and to explore several determinants of those changes. At baseline, premenopausal (PreM) women (n = 145) had lower fat body mass (FM) and greater lean body mass (LM), relative skeletal muscle mass index (RASM), and total body bone mineral content (TBBMC) compared with untreated postmenopausal (PostM) women (n = 412). During a 6-year follow-up, LM and RASM did not change, whereas a significant increase of FM and a decrease of TBBMC were observed in PreM (n = 88) and PeriM women (n = 44; women who became PostM during the follow-up). In untreated PostM women, FM increased, whereas LM, RASM, and TBBMC decreased (p < 0.0001). Age was a significant determinant of the changes in BC. After controlling for age, menopausal status was still a significant determinant only for changes in TBBMC. FM, LM, RASM, and TBBMC were higher in women with normal bone mineral density (BMD) compared with women with osteopenia or osteoporosis (p < 0.0001), but after adjusting for age, changes of BC were not significantly different according to the bone status. After controlling for age and menopausal status, levels of P1NP in the highest quartile were associated with a greater decrease of LM and RASM compared with lower levels. In conclusion, BC changes in French women over a 6-year follow-up showed a high interindividual variability. Aging may be the most important determinant of changes in body composition, rather than menopausal and bone status.

Clinical presentation of urinary tract infection (UTI) differs with aging in women

Uncomplicated UTI is among the most common health problems seen in general practice and typically affects immunocompetent, anatomically normal women. The aim of this study was to explore the difference in clinical presentation in acute, uncomplicated UTI in otherwise healthy community dwelling, premenopausal (Pre-M) and postmenopausal (Post-M) women. A UTI was defined as uropathogen of more than 103cfu/ml in midstream urine culture. Symptoms of UTI were divided to three: during voiding, local symptoms, and generalized symptoms. A total of 196 women aged a minimum of 45 years with diagnosis of UTI were studied. The patients were divided into two groups: Pre-M (n=102, mean age 48.14 years) and Post-M (n=94, mean age 69.21 years). The predominant complaints in Pre-M women were local symptoms. The clinical presentations showed more severity in the Post-M group than in Pre-M women, predominantly generalized unspecific symptoms and storage symptoms. Advanced age positively correlated with urgency of urination, painful voiding, urinary incontinence, sexual activity, low-back pain, lower abdominal pain and negatively correlated with frequency, painful and burning of urination and bladder pain. Our study showed that clinical presentation of UTI in Pre-M and Post-M women is different. The differences are presented not only by the voiding itself and by local symptoms but also by unspecified generalized symptoms that is especially important in elderly patients.

Pre- ve Post-Menopozal Kadınlar Arasında Metabolik Sendrom Prevalansı ATP III ve IDF Kriterlerine Göre Değişmekte midir?

Objective: The aims of this study were the estimation and comparison of cardiovascular risk factors and the prevalence of metabolic syndrome (MetS) among pre-menopausal (pre-M) and post-menopausal (post-M) women. Material and Methods: This study was conducted on 664 (pre-M: 378, post-M: 286) women, aged between 30-64 years. Body weight and waist circumferences (WC) were measured in all participants. Additionally, body mass index (BMI) and waist/hip ratio (WHR) were calculated, and lipid profiles were determined. Results: The mean ages of pre-M women and post-M women were found as 42.1 ± 4.50 and 56.2 ± 4.19 years, respectively (p< 0.001). Mean WC (p< 0.001), WHR (p< 0.001), systolic arterial pressure (SAP) (p< 0.001), and diastolic arterial pressure (DAP) (p< 0.001) levels were significantly higher in post-M women as compared to pre-M women. The mean fasting plasma glucose (FPG) (p= 0.005), low-density lipoprotein cholesterol (LDL-C) (p= 0.017), triglycerides (TG) (p= 0.017), and total cholesterol/high density lipoprotein cholesterol (TC/HDL-C) (p= 0.043) levels were significantly lower in pre-M women. However, TC level was significantly higher in post-M women (p< 0.001). We found a significant increase in the prevalence of the MetS among the post-menopausal women depending upon the International Diabetes Federation (IDF) and The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Conclusion: Menopause is an important risk factor for metabolic syndrome. MetS was more prevalent among postmenopausal women compared to the premenopausal women depending upon both criteria.