Premenopausal Cohort Research Articles

Retrospective Investigator-Initiated Trial on Tocopherol Acetate Vaginal Administration in Pre-and Postmenopausal Women.

Menopause, a natural phase in a woman's life, often adversely affects physical, mental, sexual, and emotional well-being due to low estrogen levels. This study examines the impact of vaginal ovules with tocopherol acetate (Filme Gyno-V® ovules, manufactured by Panin Srl and distributed by Hulka Srl, Italy), 500 mg per ovule, on vaginal health in pre- and menopausal women. Fifty women aged 50-70 were divided into menopausal (28) and premenopausal (22) cohorts and treated with the ovules for two weeks, with assessments before and after treatment. The findings showed that distressing symptoms of vaginal atrophy, such as dryness, itching, and pain during intercourse, were resolved post-treatment. A molecular analysis revealed a reduction in Escherichia coli in both cohorts and an increase in three species of Lactobacillus in premenopausal patients. This study concludes that Filme Gyno-V ovules may benefit vaginal health by alleviating atrophy symptoms and promoting healthy vaginal microbiota.

Initial ribociclib plus endocrine therapy for HR+/HER2- advanced breast cancer in pre- and postmenopausal Chinese women: Primary results from a phase 2 randomized study.

AbstractBackgroundThe MONALEESA‐7 and ‐2 phase 3 randomized trials demonstrated a statistically significant progression‐free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre‐ and postmenopausal patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre‐ and postmenopausal patients with HR+/HER2– ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA‐7 and ‐2 studies.MethodsPatients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator‐assessed PFS.ResultsAs of April 25, 2022, the median follow‐up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies.ConclusionsThese data demonstrate a favorable benefit–risk profile for ribociclib + ET in Chinese patients.

Using Machine Learning to Identify the Relationships between Demographic, Biochemical, and Lifestyle Parameters and Plasma Vitamin D Concentration in Healthy Premenopausal Chinese Women.

Vitamin D plays a vital role in maintaining homeostasis and enhancing the absorption of calcium, an essential component for strengthening bones and preventing osteoporosis. There are many factors known to relate to plasma vitamin D concentration (PVDC). However, most of these studies were performed with traditional statistical methods. Nowadays, machine learning methods (Mach-L) have become new tools in medical research. In the present study, we used four Mach-L methods to explore the relationships between PVDC and demographic, biochemical, and lifestyle factors in a group of healthy premenopausal Chinese women. Our goals were as follows: (1) to evaluate and compare the predictive accuracy of Mach-L and MLR, and (2) to establish a hierarchy of the significance of the aforementioned factors related to PVDC. Five hundred ninety-three healthy Chinese women were enrolled. In total, there were 35 variables recorded, including demographic, biochemical, and lifestyle information. The dependent variable was 25-OH vitamin D (PVDC), and all other variables were the independent variables. Multiple linear regression (MLR) was regarded as the benchmark for comparison. Four Mach-L methods were applied (random forest (RF), stochastic gradient boosting (SGB), extreme gradient boosting (XGBoost), and elastic net). Each method would produce several estimation errors. The smaller these errors were, the better the model was. Pearson's correlation, age, glycated hemoglobin, HDL-cholesterol, LDL-cholesterol, and hemoglobin were positively correlated to PVDC, whereas eGFR was negatively correlated to PVDC. The Mach-L methods yielded smaller estimation errors for all five parameters, which indicated that they were better methods than the MLR model. After averaging the importance percentage from the four Mach-L methods, a rank of importance could be obtained. Age was the most important factor, followed by plasma insulin level, TSH, spouse status, LDH, and ALP. In a healthy Chinese premenopausal cohort using four different Mach-L methods, age was found to be the most important factor related to PVDC, followed by plasma insulin level, TSH, spouse status, LDH, and ALP.

PD05-04 THE ASSOCIATION OF SELF-REPORTED RECURRENT URINARY TRACT INFECTIONS AND HORMONALLY MEDIATED VESTIBULODYNIA

You have accessJournal of UrologyCME1 Apr 2023PD05-04 THE ASSOCIATION OF SELF-REPORTED RECURRENT URINARY TRACT INFECTIONS AND HORMONALLY MEDIATED VESTIBULODYNIA Ryan Nasseri, Valencia Henry, and Maria Uloko Ryan NasseriRyan Nasseri More articles by this author , Valencia HenryValencia Henry More articles by this author , and Maria UlokoMaria Uloko More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003229.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Introduction: Hormonally mediated vestibulodynia (HMV) is a very common condition affecting up to 30% of women yet is poorly diagnosed and treated. The cause of HMV is secondary to testosterone deficiency which can be caused by various things (i.e medications, menopause, breast feeding, etc) Although the primary symptoms of HMV are associated with dyspareunia, patients with HMV often have bothersome lower urinary symptoms that are often misdiagnosed as recurrent urinary tract infections (rUTI). Both conditions have profound impact on the psychological and social well-being of patients. We hypothesize that there is a correlation between patients with self-reported rUTI and HMVObjective: The purpose of this study is to assess the correlation of self-reported rUTI and HMV. METHODS: We performed a retrospective chart review of patients over a 12-month period presenting to our vulvar sexual health clinic with a primary complaint of self-reported rUTIs We defined self-reported as a history of negative urine cultures despite positive symptoms. All patients underwent a comprehensive evaluation including a detailed history, comprehensive vulvar exam including assessment of the vestibule with a Q-tip, pelvic floor assessment, comprehensive hormone labs in premenopausal women including estrogen, testosterone, SHBG, free testosterone, FSH, LH, prolactin, TSH, urine culture, and cystoscopy /renal US if indicated by the guidelines. Patients that demonstrated vestibular tenderness on exam with correlated low free testosterone or post-menopausal status were diagnosed with HMV. RESULTS: There was a total of 107 patients seen for evaluation of self-reported rUTIs. The median age was 57. 55.1% (59/107) of patients were post-menopausal and 44.9% (48/107) pre-menopausal. Of the 107 patient, 64 (60%) were diagnosed with HMV. When stratifying for menopause status, 50% of the menopausal cohort were diagnosed with HMV and 73% of the premenopausal cohort were diagnosed with HMV. The average free testosterone of the premenopausal women was 0.23 ng/dl (goal=0.8ng/dl). CONCLUSIONS: There is a high correlation between HMV and lower urinary tract symptoms. Further studies are needed to elicit if treatment of HMV can eradicate symptoms of lower urinary tract symptoms in certain demographics. Source of Funding: N/a © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e149 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryan Nasseri More articles by this author Valencia Henry More articles by this author Maria Uloko More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract P6-05-06: Patient-reported anxiety and fatigue in women enrolled in the RxPONDER trial (SWOG S1007) by menopausal status

Abstract Introduction: Anxiety and fatigue have been reported by women undergoing cytotoxic and endocrine treatment (tx) for breast cancer and can have lasting effects on quality of life (QoL). The differential effects of menopausal (meno) status, tx allocation and duration of symptoms are not well established. Methods: Participants (pts) with hormone receptor positive, HER2 negative breast cancer with 1-3 positive lymph nodes and an Oncotype DX recurrence score of 0-25 enrolled in the RxPONDER trial were randomly assigned to endocrine therapy (ET) alone vs chemotherapy followed by ET (CET). A subset of English speaking pts in the US at the start of the trial were invited to complete health-related QoL (HRQoL) questionnaires shortly after randomization (baseline; BL) and 6, 12, and 36 months after BL until accrual goal reached. BL surveys were completed in clinic; cognitive function results presented separately. Standardized T scores (mean 50; SD 10) were computed for anxiety (PROMIS Emotional Distress – Anxiety Short Form 7a) and fatigue (PROMIS Fatigue Short Form 7a). Higher T scores indicate more anxiety or fatigue. The primary endpoint of this exploratory analysis was to compare mean anxiety and fatigue T score by tx arm by meno status. Separately by meno status, a GEE model was fit to the three follow-up timepoints adjusting for BL to estimate the difference between tx arms and whether there was a time trend over the three follow-up measures. Results: The accrual exceeded the goal of 500 pts with 74% of pts participating voluntarily until the QOL invitation was removed from the protocol (12/1/12). A total of 139 pre and 432 postmenopausal pts completed the anxiety questionnaire at BL. There was no difference in anxiety between tx arms [Table 1]. Mean anxiety score difference between CET and ET over time in the premenopausal cohort was -0.63 (p=0.63) and in the postmenopausal cohort was 0.59 (p=0.45). Although anxiety scores decreased over the three follow-up times, the change was not statistically significant. A total of 139 pre and 429 postmenopausal pts completed the fatigue questionnaire at BL. Fatigue mean T scores in both the pre and postmenopausal cohorts were higher over time in the CET vs ET arm [Table 2]. Fatigue scores were 2.85 points higher for CET vs. ET over time in the premenopausal cohort (p=0.02) and 1.82 points higher in the postmenopausal cohort (p=0.007). Fatigue scores decreased over time for premenopausal (p=0.01), but not for postmenopausal (p=0.62) pts. Dropoff occurred over time with 79%, 76%, 60% of pts at BL participating at 6, 12, and 36 months. Endocrine treatment adherence data are not yet available at each timepoint. Conclusions: CET had a clinically significant negative effect on mean fatigue scores compared to ET alone in both pre and postmenopausal pts over time. Scores improved over time but did not return to BL. Pts had lower mean anxiety scores during tx compared to BL, but differences in scores between CET and ET groups out to 3 years did not significantly differ. Future therapeutic studies must continue to include HRQoL assessments to broaden our understanding of the full impact of chemotherapy and for the development of preventative and therapeutic strategies to manage these toxicities. Table 1. Comparisons of mean Anxiety score by treatment arm and menopausal status. Table 2. Comparisons of mean Fatigue score by treatment arm and menopausal status. Citation Format: Michelle M. Loch, Jamie K. Forschmiedt, Irene M. Kang, Julie R. Gralow, Funda Meric-Bernstam, Kathy S. Albain, Daniel F. Hayes, Nancy U. Lin, Edith A. Perez, Lori J. Goldstein, Priya Rastogi, Anne F. Schott, Steven Shak, Priyanka Sharma, Danika L. Lew, Jieling Miao, William E. Barlow, Debu Tripathy, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky, N. Lynn Henry. Patient-reported anxiety and fatigue in women enrolled in the RxPONDER trial (SWOG S1007) by menopausal status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-06.

Assessment of endothelial dysfunction and inflammation in type 2 diabetic postmenopausal women

Objective: Vascular complications in type 2 diabetes mellitus are an important cause of morbidity and mortality. Also, endothelial dysfunction arises with vascular ageing during the postmenopausal period. Our objective in this study was to evaluate inflammation and endothelial function parameters and their possible diagnostic roles in type 2 diabetic postmenopausal patients. Material and Methods: The study was conducted on four groups, including type 2 diabetic premenopausal (n:20), non-diabetic premenopausal (n:20), type 2 diabetic postmenopausal (n:20), and non-diabetic postmenopausal subjects (n:20). Serum endothelin-1 (ET-1), endothelial nitric oxide synthetase (eNOS), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and chitinase-3-like protein 1 (YKL-40) levels were determined as inflammatory and endothelial function markers using ELISA kits. Results: Serum ET-1, IL-6, and YKL-40 levels were higher in the type 2 diabetic postmenopausal group compared to the non-diabetic premenopausal group (p<0.01, p<0.05, and p<0.01, respectively). ET-1, IL-6, and YKL-40 levels were higher in the type 2 diabetic postmenopausal group compared to the non-diabetic postmenopausal group (p<0.001, p<0.05, and p<0.01 respectively). ROC analysis revealed serum ET-1 (AUC 0.933, sensitivity 87.5%, specificity 85.7%), IL-6 (AUC 0.812, sensitivity 56.3%, specificity 92.8%), and YKL-40 (AUC 0.880, sensitivity 81.2%, specificity 92.8%), as good diagnostic parameters, especially in the type 2 diabetic premenopausal vs. non-diabetic premenopausal cohorts. Conclusion: Serum ET-1, IL-6, and YKL-40 levels were at the highest levels in the 2 diabetic postmenopausal group, and the increase in these markers was remarkable in diabetes compared with menopausal periods. Also, ET-1, IL-6, and YKL-40 were good diagnostic parameters for detecting endothelial function and inflammation in type 2 diabetic postmenopausal and non-diabetic premenopausal cohorts.

Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder.

Flibanserin treatment increases sexual desire and satisfying sexual events while decreasing distress in certain women diagnosed with acquired, generalized hypoactive sexual desire disorder (HSDD). Additional aspects of sexual function and the time course of response have not been fully characterized. To evaluate changes in sexual function assessed by the subdomains of the Female Sexual Function Index (FSFI) in women with HSDD treated with flibanserin. FSFI data pooled from 3 pivotal flibanserin trials in premenopausal women (flibanserin=1,165; placebo=1,203) and FSFI data from one complete flibanserin trial in postmenopausal women (flibanserin=432; placebo=463) were subjected to post-hoc analyses. For each FSFI subdomain, least squares mean change from baseline was calculated at each assessment visit (treatment weeks 4, 8, 16, 24) and treatment groups were compared using analysis of covariance. Standardized effect size (Cohen's d) was also determined for each FSFI subdomain. Changes from baseline in FSFI subdomains. Compared to placebo, both premenopausal (P < .02) and postmenopausal (P < .045) patients in the flibanserin group reported significantly greater increases over baseline in the FSFI subdomain scores of desire, arousal, lubrication, orgasm, and satisfaction. In premenopausal patients, significant improvements were observed at the first assessment of response (week 4) and were maintained through week 24. In postmenopausal patients, significant improvements were observed at week 4 for desire and arousal, while significant improvements in lubrication, orgasm, and satisfaction were observed at week 8. At week 24, excluding the pain subdomain, standardized effect sizes ranged from 0.18 to 0.28 in the premenopausal cohort and 0.12 to 0.29 in the postmenopausal cohort. In both pre- and postmenopausal patients, improvements in pain were smaller and largely undifferentiated between treatment groups. While variations in time to response should be taken into consideration, on average, the beneficial impact of flibanserin on overall sexual function occurs within the first month of treatment. The data also suggest that the response to flibanserin is sustained for the duration of treatment. Sexual function assessments were performed in a large cohort of 2,368 premenopausal women and 895 postmenopausal women. However, the FSFI assesses changes over a 1-month period and time points earlier than 4 weeks could not be assessed. These analyses suggest that assessment of benefit of flibanserin in HSDD should include improvements across all domains of sexual function, not only desire. Simon JA, Clayton AH, Goldstein I, et al. Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder. Sex Med 2022;10:100570.

The Comparison of Three Predictive Indexes to Discriminate Malignant Ovarian Tumors from Benign Ovarian Endometrioma: The Characteristics and Efficacy.

This study aimed to evaluate the prediction efficacy of malignant transformation of ovarian endometrioma (OE) using the Copenhagen Index (CPH-I), the risk of ovarian malignancy algorithm (ROMA), and the R2 predictive index. This retrospective study was conducted at the Department of Gynecology, Nara Medical University Hospital, from January 2008 to July 2021. A total of 171 patients were included in the study. In the current study, cases were divided into three cohorts: pre-menopausal, post-menopausal, and a combined cohort. Patients with benign ovarian tumor mainly received laparoscopic surgery, and patients with suspected malignant tumors underwent laparotomy. Information from a review chart of the patients’ medical records was collected. In the combined cohort, a multivariate analysis confirmed that the ROMA index, the R2 predictive index, and tumor laterality were extracted as independent factors for predicting malignant tumors (hazard ratio (HR): 222.14, 95% confidence interval (CI): 22.27–2215.50, p < 0.001; HR: 9.80, 95% CI: 2.90–33.13, p < 0.001; HR: 0.15, 95% CI: 0.03–0.75, p = 0.021, respectively). In the pre-menopausal cohort, a multivariate analysis confirmed that the CPH index and the R2 predictive index were extracted as independent factors for predicting malignant tumors (HR: 6.45, 95% CI: 1.47–28.22, p = 0.013; HR: 31.19, 95% CI: 8.48–114.74, p < 0.001, respectively). Moreover, the R2 predictive index was only extracted as an independent factor for predicting borderline tumors (HR: 45.00, 95% CI: 7.43–272.52, p < 0.001) in the combined cohort. In pre-menopausal cases or borderline cases, the R2 predictive index is useful; while, in post-menopausal cases, the ROMA index is better than the other indexes.

Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin.

BackgroundThe efficacy of flibanserin in treating hypoactive sexual desire disorder (HSDD) is based upon statistically significant improvements in sexual desire, satisfying sexual events, and distress. However, clinically meaningful benefit has not been well characterized.AimEvaluate clinically meaningful benefit of flibanserin.MethodsData were pooled from 3 pivotal trials evaluating flibanserin 100 mg qhs in premenopausal women (flibanserin, n = 1192; placebo, n = 1215). Flibanserin trial data in postmenopausal women (flibanserin, n = 450; placebo, n = 476) were analyzed separately. Clinically meaningful benefit was evaluated by the Patient Global Impression of Improvement (PGI-I). Responders were determined through anchor-based analyses that used the PGI-I for key efficacy endpoints: satisfying sexual events (SSE), desire domain of the Female Sexual Function Index (FSFI-d), and distress associated with decreased sexual desire (FSDS-R13). Odds ratios were calculated to assess effect size and Kaplan-Meier analyses were performed to estimate onset time for treatment benefit.OutcomesPGI-I, anchor-based analyses for key efficacy endpoints (SSE, FSFI-d, FSDS-R13), odds ratios, onset time for treatment benefit.ResultsBased on the PGI-I, more patients reported clinically meaningful benefit with flibanserin treatment versus placebo (49.8% vs 33.6%, premenopausal cohort; 40.5% vs 28.7%, postmenopausal cohort). In anchor-based analyses, responder rates were significantly higher for premenopausal women on flibanserin (46.1%–55.2%) than placebo (34.1%–44.2%) for all 3 key efficacy endpoints (P < .0001). Responder rates for postmenopausal women on flibanserin were higher compared to placebo for SSE (29.8% vs 22.9%; P = .015) and FSFI-d (38.9% vs 26.3%; P = .0001). Odds ratios for key endpoints indicated that premenopausal women were 2.0–2.4 times as likely to be responders with flibanserin treatment compared to placebo. Postmenopausal women were 1.6 times as likely to be responders with flibanserin for FSFI-d. Kaplan-Meier analyses indicated significant separation between flibanserin and placebo for the key endpoints in both premenopausal and postmenopausal cohorts (log-rank tests P < .01) with earlier median response times among patients receiving flibanserin.Clinical ImplicationsPatient-reported benefit assessments such as the PGI-I capture the patient's perspective and may be a useful approach in assessing overall clinical meaningfulness for sexual dysfunction therapies.Strengths and LimitationsStrengths include a well-powered study with large enrollment, use of validated instruments, and self-assessment of treatment benefit. Limitations include pooling of trial data in premenopausal women with slightly different study designs and use of an endpoint (SSE) indirectly related to HSDD.ConclusionAssessment of clinically meaningful benefit and additional responder analyses provide further support for flibanserin's efficacy beyond numerical improvements in endpoint measures.Simon JA, Clayton AH, Kim NN, et al. Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin. Sex Med 2022;10:100476.

Ovarian function suppression as a potential mechanism of chemotherapy.

Ovarian function suppression as a potential mechanism of chemotherapy.

Endocan as a predictor of increased cardiovascular risk during the menopausal transition period.

Our aim was to investigate the serum endocan levels and carotid artery intima-media thickness (CIMT) measurements of pre- and postmenopausal patients to clarify the relationship between the menopausal transition and endothelial injury. This cross-sectional study was conducted on women who were premenopausal and postmenopausal between January 2019 and June 2019. The patients were divided into two groups according to premenopausal (n = 32) and postmenopausal (n = 32) status. Serum endocan levels were assessed by enzyme-linked immunosorbent assay (ELISA). CIMT ultrasonographic measurements were determined. Hormonal and biochemical parameters were measured. The validated Menopause Rating Scale (MRS) questionnaire was used on all women. Serum endocan levels were significantly higher in the postmenopausal group than in the premenopausal group (222.90 ± 121.00ng/L and 146.62 ± 41.88ng/L, p = 0.033, respectively). The mean CIMT was significantly higher in the postmenopausal group than in the premenopausal cohort (0.70 ± 0.14mm and 0.58 ± 0.11mm, p < 0.001, respectively). A positive correlation was found between body mass index (BMI), systolic blood pressure (SBP), abdominal circumference (AC), and CIMT and postmenopausal serum endocan levels. Serum endocan levels with a cutoff point of 141.14ng/L identified women with significant CIMT levels with sensitivity of 73.8% and specificity of 77.3%. A positive correlation was found between CIMT and endocan and total MRS scores. Serum endocan levels were associated with CIMT during the menopausal transition period. Increased circulating endocan levels can be a predictor of cardiovascular risk in pre- and postmenopausal women.

Abstract OT2-02-08: A phase 2 randomized, double-blind, placebo-controlled study of ribociclib or placebo in combination with endocrine therapy for the treatment of premenopausal and postmenopausal Chinese women with HR+, HER2−, advanced breast cancer

Abstract Background: Ribociclib (RIB) is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that has demonstrated efficacy and safety in combination with endocrine therapy (ET) for the treatment of advanced breast cancer (ABC), but to date no studies have specifically evaluated RIB in a population in mainland China. This study aims to assess the efficacy and safety of RIB or placebo in combination with ET in premenopausal and postmenopausal Chinese patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2−) ABC. It is also designed to investigate the pharmacokinetics (PK) of RIB in combination with ET. Methods: In this phase 2 randomized, double-blind, placebo-controlled study, Chinese women with ABC will be included in a premenopausal or postmenopausal cohort (~150 patients each) and randomized 1:1 in each cohort to receive RIB or placebo. A further ~15 patients will be included in an open-label PK cohort. All patients must have HR+, HER2− ABC based on the most recently analyzed biopsy, with advanced disease not amenable to curative therapy. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (version 1.1) or at least 1 predominantly lytic bone lesion, and Eastern Cooperative Oncology Group performance status score (ECOG PS) &amp;lt; 2. Patients in the premenopausal cohort must be adult women who received no prior hormonal therapy and ≤ 1 line of chemotherapy (CT) for ABC and are eligible for ET. Patients in the postmenopausal and PK cohorts must be postmenopausal women who received no prior therapy (ET or CT) for ABC and are eligible for ET; patients who have received (neo)adjuvant therapy are eligible - if the prior neo(adjuvant) therapy included letrozole or anastrozole, the disease-free interval must be &amp;gt; 12 months from the completion of treatment until randomization. Exclusion criteria include previous CDK4/6 inhibitor therapy; symptomatic visceral disease or any disease burden rendering patients ineligible for ET; central nervous system metastases; known human immunodeficiency virus infection history; and clinically significant uncontrolled heart disease. Patients in the premenopausal cohort will be randomized to 600 mg RIB oral (3 weeks on/1 week off) or placebo, in combination with a nonsteroidal aromatase inhibitor (2.5 mg letrozole [LET] oral or 1 mg anastrozole oral, chosen by investigator) and 3.6 mg goserelin subcutaneous. Patients in the postmenopausal cohort will receive RIB or placebo in combination with LET; those in the single-arm PK cohort will receive RIB in combination with LET. The primary endpoint of the premenopausal and postmenopausal cohorts is progression-free survival. Secondary endpoints are overall survival, overall response rate, clinical benefit rate, time to response, duration of response, and time to deterioration in ECOG PS. The objectives for the PK cohort are to characterize PK parameters of the RIB + LET combination, and of the RIB metabolites. Citation Format: Zhimin Shao, Binghe Zu, Zhongsheng Tong, Qiang Liu, Wei Li, Li Cai, Kunwei Shen, Wenhe Zhao, Jin Yang, Chuan Wang, Woody Tang, Tingting Sun, Yu Han, Ruina Gao. A phase 2 randomized, double-blind, placebo-controlled study of ribociclib or placebo in combination with endocrine therapy for the treatment of premenopausal and postmenopausal Chinese women with HR+, HER2−, advanced 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 OT2-02-08.

Abstract GS4-03: Validation of the clinical treatment score post 5 years (CTS5) in women with hormone receptor positive, HER2-negative, node-negative disease from the TAILORx study

Abstract Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological parameters (nodal status, tumor size, grade, and age) to estimate distant recurrence (DR) risk after 5 years of endocrine treatment for postmenopausal women with estrogen receptor (ER) positive breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Here, we evaluate whether the CTS5 is prognostic in women who were distant recurrence (DR) free 5 years after adjuvant treatment who participated in the TAILORx study. Methods: 10273 women with ER-positive, HER2-negative, and node-negative disease were entered into the TAILORx study and assigned or randomized to four treatment arms according to their Oncotype Recurrence Score (RS) (endocrine therapy alone (ET) or chemo-endocrine therapy (CET)). Primary endpoint of this analysis was DR and the primary objective of this analysis was to evaluate the CTS5 in the TAILORx study, stratified by chemotherapy use. Secondary objectives included validation of the CTS5 in two specific age groups (age≤50 years vs. age&amp;gt;50 years) and in the four separate treatment arms. Cox regression models were used to determine the prognostic value of CTS5. Kaplan-Meier curves were used to estimate conditional 9-year DR risks (%). Hazard ratios are reported for an increase of 1-standard deviation of CTS5 in the overall analysis population. Results: 7353 (71.6%) women were DR free 5 years after diagnosis with follow-up beyond 5 years, had information for all clinical parameters, and were included in this analysis. Median follow-up after 5 years was 2.9 years (1.8-3.9). Overall, mean age was 55.7 years (SD 9.0), mean tumor size 17.1mm (SD 7.8), and the vast majority had low or moderately differentiated disease (84.7%). CTS5 was significantly higher for women in arm D (RS 26-100, CET) compared to the other three arms (mean CTS5 3.09 vs. 2.82, P&amp;lt;0.001). Overall, CTS5 was highly prognostic for late DR stratified for assigned chemotherapy arm (HR=1.57 (1.36-1.82), P&amp;lt;0.0001) (Table). 5385 (72.9%) of women were categorised into the low risk group by CTS5, 1836 (25.0%) into the intermediate risk group, and 132 (2.1%) into the high risk group. Looking at each arm separately, CTS5 did not predict late DR in women with RS 0-10 and ET (arm A), but provided strong prognostic information for late DR in arms B (RS 11-25, ET), C (RS 11-25, CET), and D (RS 26-100, CET) (Table). CTS5 strongly predicted late DR in women who were older than 50 years (HR=1.78 (1.48-2.14), P&amp;lt;0.0001), but to a smaller extent in women aged 50 years or younger (HR=1.35 (1.01-1.82), P=0.046) (Table). Conclusions: Low risks of late DR of 3.1% (2.4-4.0) for RS scores 0-25 (ET) and 3.8% (2.9-4.8) for RS scores 11-100 (CET) were observed in this ER-positive, HER2-negative and node negative TAILORx cohort. We confirm the prognostic ability of the CTS5 for late DR in the TAILORx cohort, specifically for patients older than 50 years and/or those who were deemed intermediate or high risk by Oncotype Dx RS (11-100). Our results show that the CTS5 is less prognostic for late DR in women aged 50 years or younger who received 5 years of endocrine therapy only. Further evaluation of the CTS5 in premenopausal cohorts is needed before it can be applied to younger patients. Table: Hazard Ratios (95% CI) for prognostic value of CTS5 overall and according to sub-groups.HR (95% CI )P-valueAll (N=7353)1.57 (1.36-1.82)&amp;lt;0.0001Arm A (N=1323)1.34 (0.87-2.07)0.19Arm B (N=2746)1.50 (1.17-1.93)0.002Arm C (N=2655)1.56 (1.22-1.98)0.0003Arm D (N=629)1.90 (1.23-2.92)0.004Age ≤ 50 years (N=2259)1.35 (1.01-1.82)0.046Age &amp;gt; 50 years (N=5094)1.78 (1.48-2.14)&amp;lt;0.0001 Citation Format: Ivana Sestak, Michael Crager, Jack Cuzick, Mitchell Dowsett, Steven Shak, Gong Tang, Robert Gray, Joseph Sparano. Validation of the clinical treatment score post 5 years (CTS5) in women with hormone receptor positive, HER2-negative, node-negative disease from the TAILORx study [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 GS4-03.

Abstract PD8-03: Clinico-pathological and molecular features in young women with metastatic breast cancer

Abstract Introduction: Advanced breast cancer can be more aggressive and portend a worse prognosis in the younger population (age &amp;lt; 50). While several studies have outlined clinico-pathologic features and molecular features of primary disease in young women with breast cancer, data in the metastatic setting remain scarce. Thus, the goal of this study was to explore the underlying clinic-pathologic and molecular profile of young women with metastatic breast cancer. Methods: We conducted a retrospective analysis of 138 females with metastatic breast cancer treated at Northwestern Medicine who provided consent for serial evaluation of circulating biomarkers. Patient were divided into two cohorts based on age at the time of metastasis, namely premenopausal (defined as age &amp;lt; 50) and postmenopausal (age ≥ 50). CellSearch™ immunomagnetic kit (Menarini Silicon Biosystems) was utilized to enumerate circulating tumor cells (CTCs), and the CellSearch™ CXC Kit (in 7.5 cc whole blood) characterized CTC HER2 expression. Circulating tumor DNA (ctDNA) was sequenced using the Guardant360 next-generation sequencing (NGS) assay (Guardant Health). When available, tissue samples from the primary and metastatic site(s) were sequenced using FoundationOne and/or Tempus xT NGS assays. Associations were drawn using Pearson’s χ2 test, independent samples T-tests, and multivariate logistic regression. Results: Of the 138 women, 54 (39%) were premenopausal with median age of 42 (range: 28-49), and 84 (61%) were postmenopausal with median age of 57 (range: 50-81). For the premenopausal cohort, 96% had invasive ductal carcinoma, 2% invasive lobular carcinoma and 2% mixed/unknown, compared to postmenopausal with 74%, 19% and 7% respectively, p=0.003. No statistically significant association was observed based on disease subtype (HR+/HER2-, HR+/HER2+, HR-/HER2+, TNBC), correspondingly stratified as 46%, 17%, 9%, 28% (premenopausal) and 57%, 10%, 13% 20% (postmenopausal). In total, 39% of the premenopausal and 40% of the postmenopausal patients had inflammatory breast cancer (IBC). Among patients initially diagnosed with non-metastatic disease, time (years) to metastasis was 2.76 (95% CI 2.11 to 3.41) for the premenopausal and 6.08 (95% CI 4.89 to 7.27) for the postmenopausal cohort, p=0.0001. Statistically significant associations were found when comparing the NGS datasets, derived from serial collection of ctDNA +/- tissue samples. Specifically, the premenopausal group had a higher incidence of GATA3 (11 vs 6 cases; p=0.017) alterations, but a lower incidence of NF1 (1 vs 18; p&amp;lt;0.001) and RB1 (1 vs 9; p=0.049) alterations. Most common gene alterations included TP53 (67%), PIK3CA (45%), ERBB2 (26%), GATA3 (26%), MYC (24%), FGFR1 (19%) and ESR1 (17%) for the younger cohort, versus TP53(67%), PIK3CA (39%), ESR1 (27%), NF1 (27%), MYC (23%), ERBB2 (23%) and FGFR1 (20%) for the postmenopausal cohort. There were no statistically significant differences between the cohorts in terms of total number of ctDNA alterations at baseline draw (median[IQR]: 3[1-7] premenopausal group; 5[2-7] postmenopausal group), presence of ≥5 CTCs (54%; 46% of total cases, respectively), occurrence of CTC clusters (26%; 24%), or HER2+ CTC expression (44%; 45%). Conclusion: Our data reveal that premenopausal women diagnosed with metastatic breast cancer had a more rapid progression to metastasis and differ from their postmenopausal counterparts in both their pathologic profile (almost exclusively invasive ductal carcinoma) and molecular profile (notably, gene alteration frequencies of NF1, RB1 and GATA3), which could have significant implications in developing targeted treatment paradigms for younger women. Additionally, CTC prevalence in the metastatic setting differs from earlier stage breast cancer data showing a higher proportion of ≥5 CTCs in postmenopausal patients. Citation Format: Kristen Carroll, Ami M Shah, Lorenzo Gerratana, Chenyu Lin, Andrew A Davis, Qiang Zhang, Youbin Zhang, Lisa Flaum, Amir Behdad, Leonidas C Platanias, William J Gradishar, Massimo Cristofanilli. Clinico-pathological and molecular features in young women with metastatic 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 PD8-03.

Adjuvant endocrine therapy for premenopausal women: risk stratification, type and duration

Updated results from the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) have helped to identify differential value of various adjuvant endocrine therapy strategies in high-risk and low-risk premenopausal early breast cancer. With a median follow-up of 8 years in SOFT, there is now a significant improvement in disease-free survival (DFS) for those assigned to receive 5 years of tamoxifen plus ovarian function suppression (T + OFS) as compared with tamoxifen (T). Further improvement in DFS was observed for those assigned exemestane plus OFS (E + OFS). While the relative treatment effect from the addition of OFS to tamoxifen in the no chemotherapy and prior chemotherapy cohorts in SOFT was similar, larger absolute improvement in DFS was observed with endocrine therapy escalation in the premenopausal cohort who had received chemotherapy. Despite some improvement in DFS in the lower risk no-chemotherapy cohort, the 8-year results for that cohort continue to show a low risk of distant metastases with the use of adjuvant tamoxifen as sole systemic therapy. A small overall survival advantage from the addition of OFS to tamoxifen has now emerged in SOFT, which appears more clinically meaningful in the prior chemotherapy cohort.In the joint analysis of SOFT and TEXT, there is currently no overall survival improvement at 8 years for those assigned E + OFS versus T + OFS, despite a significant reduction in distance recurrences with E + OFS. Assessing absolute improvements in freedom from distant recurrence observed with the different endocrine strategies across the risk spectrum of patients with HER2-negative tumours in SOFT and TEXT, may assist decision-making for premenopausal patients.

RIBECCA: A phase IIIb, multicenter, open label study for women with estrogen receptor-positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole—Results of the second interim analysis.

1061 Background: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7. Here we present the results of the second preplanned interim analysis. Methods: Main inclusion criteria allowed enrollment of men or women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, and histological or cytological confirmation of ER+, HER2- breast cancer, irrespective of their menopausal status. The primary objective is to assess the clinical benefit rate (CBR) after 6 months. Secondary objectives include: progression free survival (PFS), overall survival (OS), safety and changes in quality of life. Results: The cut-off date for this second interim analysis was 12 months after the last patient was enrolled in the pretreated and premenopausal cohort. Here we report a preliminary analysis on safety, efficacy and quality of life. We describe the baseline characteristics, safety data and the clinical benefit rate (CBR) at 24 weeks, of patients (pts) with at least 24 weeks follow up (n = 411). The median observation time for all patients in this analysis was 8.1 months. Baseline characteristics: of 411 pts, 409 were female and 2 male. Median age: 64 yrs; 46 pts pre-or perimenopausal, 363 postmenopausal; ECOG 0-1: 97.0%; median time since first recurrence: 1.6 months; 72.5 % pts had bone metastases (40.6% bone only), 30.7% liver, 27.3% lung and 29.2% other metastases. Median relative dose intensity was 0.905 for ribociclib and 1 for letrozole. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (54.5%), nausea (40.6%), fatigue (36.5%), alopecia (32.6%), leukopenia or WBC decreased (29%), nasopharyngitis (23.1%), diarrhea (21.4%), ALT increased (20.7%), AST increased (19%). The CBR by week 24 was 67.6%. Preliminary information on quality of life will be provided. Conclusions: The results of the second interim analysis in this additional patient population are in line with data published from the pivotal phase III studies MONALEESA-2, MONALEESA-3 and MONALEESA-7. Clinical trial information: NCT03096847.

Clinical validity of CTS5 for estimating risk of late recurrence in unselected, non-trial patients with early ER+ breast cancer.

514 Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological data to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with estrogen receptor positive (ER+) breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Methods: The validity of CTS5 was tested in a retrospective cohort of unselected, non-trial patients diagnosed with early ER+ breast cancer at the Royal Marsden Hospital from 2000-2007 who were alive and distant recurrence-free at 5 years. The primary endpoint was time to late DR (5-10 years). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated 10-year DR risks (%). Results: A total of 2428 women were included with a median follow-up of 9.34 years from diagnosis. The CTS5 was significantly prognostic for late DR in post- and premenopausal women (Table). Risk stratification by CTS5 of the postmenopausal cohort was comparable with the development cohort. 42.1% of postmenopausal women were categorised into the low risk group with a late DR risk of 4.9% and these women had significantly lower risk of late DR compared to those in the intermediate or high-risk groups (Table). Amongst the premenopausal cohort, 41% were categorised as low risk with a late DR risk of 4.9%. The prognostic effect of CTS5 was seen for chemotherapy treated (HR=2.26, 95% CI (1.68-3.03)) and untreated patients (HR=1.93, 95% (1.32-2.82)). Conclusions: CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected, non-trial patients that included premenopausal women. The low risk cohort identified by the CTS5 represents a group of women whose risk of late DR is so low as to not warrant extended endocrine therapy to ten years. [Table: see text]

Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis

Yang et al1Yang J.D. et al.Clin Gastroenterol Hepatol. 2017; 15 (1271–31 e2)Google Scholar on behalf of the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network reviewed the liver biopsies of premenopausal women with NASH. They have demonstrated high Nonalcoholic Fatty Liver Disease Activity Score (NAS) scores in these women compared with men or postmenopausal women. The authors noted that this population of premenopausal women exhibits a better prognosis than postmenopausal women or men, while showing that the fibrosis scores in the premenopausal cohort were lower as well. The NAS score, which evaluates steatosis, lobular inflammation, and ballooning hepatocyte degeneration, is the standard method of identifying NASH for clinical studies because of its reproducibility. However, the NAS score has been demonstrated to be inaccurate in any given patient for the diagnosis of NASH.2Brunt E.M. et al.Hepatology. 2011; 53: 810-820Google Scholar, 3Wong V.W.-S. et al.Aliment Pharmacol Ther. 2011; 34: 494-495Google Scholar, 4Hjelkrem M. et al.Aliment Pharmacol Ther. 2011; 34: 495-496Google Scholar Moreover, the NAS score been shown to be a weak surrogate for NASH prognosis.5Ekstedt M. et al.Scand J Gastroenterol. 2012; 47: 108-115Google Scholar, 6Sebastiani G. et al.PLoS One. 2015; 10: e0128774Google Scholar, 7Younossi Z.M. et al.Hepatology. 2011; 53: 1874-1882Google Scholar, 8Hannah Jr., W.N. et al.Gastroenterol Hepatol (N Y). 2016; 12: 756-763Google Scholar Histologically, hepatic fibrosis is the most predictive prognosticator.9Angulo P. et al.Gastroenterology. 2015; 149 (e10): 389-397Google Scholar, 10Ekstedt M. et al.Hepatology. 2015; 61: 1547-1554Google Scholar The strongest prognostic finding of the 3 elements of the NAS score was ballooning degeneration, which ironically is underweighted when compared with fat or lobular inflammation in the NAS score.9Angulo P. et al.Gastroenterology. 2015; 149 (e10): 389-397Google Scholar Consequently, we think that using the adjective “worse” is misleading in this context. The present study indeed demonstrates once again that fibrosis and not the NAS score is the better prognosticator in NASH. Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic SteatohepatitisClinical Gastroenterology and HepatologyVol. 15Issue 1PreviewSex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. Full-Text PDF ReplyClinical Gastroenterology and HepatologyVol. 16Issue 10PreviewWe appreciate the letter from Dr Smith et al regarding our recent publication.1,2 We agree that the most significant histologic feature of nonalcoholic fatty liver disease (NAFLD) is the degree of fibrosis, which predicts long-term clinical outcome in patients with NAFLD3–5 We also agree that the NAFLD activity score (NAS), although useful for clinical research in nonalcoholic steatohepatitis, is not an ideal prognosticator of outcomes for patients with NAFLD.3–5 The NAS was developed in 2005 to provide a standardized scoring system for clinical trials, and was created to encompass the full spectrum of NAFLD histology in both adults and children. Full-Text PDF

Serum caffeine and paraxanthine concentrations and menstrual cycle function: correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study

Clinicians often recommend limiting caffeine intake while attempting to conceive; however, few studies have evaluated the associations between caffeine exposure and menstrual cycle function, and we are aware of no previous studies assessing biological dose via well-timed serum measurements. We assessed the relation between caffeine and its metabolites and reproductive hormones in a healthy premenopausal cohort and evaluated potential effect modification by race. Participants (n = 259) were followed for ≤2 menstrual cycles and provided fasting blood specimens ≤8 times/cycle. Linear mixed models were used to estimate associations between serum caffeine biomarkers and geometric mean reproductive hormones, whereas Poisson regression was used to assess risk of sporadic anovulation. The highest compared with the lowest serum caffeine tertile was associated with lower total testosterone [27.9 ng/dL (95% CI: 26.7, 29.0 ng/dL) compared with 29.1 ng/dL (95% CI: 27.9, 30.3 ng/dL), respectively] and free testosterone [0.178 ng/mL (95% CI: 0.171, 0.185 ng/dL) compared with 0.186 ng/mL (95% CI: 0.179, 0.194 ng/dL), respectively] after adjustment for age, race, percentage of body fat, daily vigorous exercise, perceived stress, depression, dietary factors, and alcohol intake. The highest tertiles compared with the lowest tertiles of caffeine and paraxanthine were also associated with reduced risk of anovulation [adjusted RRs (aRRs): 0.39 (95% CI: 0.18, 0.87) and 0.40 (95% CI: 0.18, 0.87), respectively]. Additional adjustment for self-reported coffee intake did not alter the reproductive hormone findings and only slightly attenuated the results for serum caffeine and paraxanthine and anovulation. Although reductions in the concentrations of total testosterone and free testosterone and decreased risk of anovulation were greatest in Asian women, there was no indication of effect modification by race. Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women.

Met and its ligand HGF are associated with clinical outcome in breast cancer.

Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo- or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre- and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the pre-menopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.