Postmenopausal Breast Cancer Patients Research Articles

Comparison of Clinicopathological Features between Premenopausal and Postmenopausal Female Breast Cancer Patients in Kurdistan Region of Iraq: A Retrospective Single Institution Study of 671 Female Patients

Introduction: Breast cancer is the most common cancer in women, and its incidence is increasing annually worldwide. It accounts for 24% of new cancer cases and 15% of cancer deaths in 2018, and according to the GLOBOCAN Cancer Tomorrow prediction tool, incident cases are expected to increase by more than 46% by 2040. Studies carried out thus far have shown that risk factors and histopathological features of breast malignancies may vary among different age groups. Menopausal status is an essential factor influencing clinicopathological characteristics of patients with breast cancer. Prognostic factors are used to estimate how aggressive the tumor may evolve and to decide on a treatment approach. In Iraq, breast cancer is most frequently seen in younger women in their fourth and fifth decades of life, who often show in advanced stages at the time of diagnosis, according to previous surveys. Objectives: The main objective of this study was to assess the clinicopathologic features between premenopausal and postmenopausal breast cancers to provide valuable insights into what may influence the age at diagnosis of breast cancer in the Kurdistan region of Iraq. Methods: This retrospective study included 671 non-metastatic breast cancer patients referred to Zhianawa Cancer Center between January 2015 and December 2017. Disease stage was determined using the American Joint Committee on Cancer and Union for International Cancer Control (UICC) (“Tumour,” “Nodes,” “Metastases”) TNM systems. The patients were divided into premenopausal and postmenopausal groups. The chi-square test was used to evaluate the association between the variables. Results: The mean age of the participants was 47.5 years. The most prevalent age group was 40-49, followed by the age group 50-59. Of the participants, 60.5% were premenopausal, and 39.4% were postmenopausal. Stage IIIA was the most common stage at diagnosis. At the same time, the most minor stage at diagnosis was stage 0. The second most common stage was IIB. There was a strong association between menopausal status with grade (P value 0.001) and LVI (P value 0.01); however, there was a non-significant correlation between menopausal status and stage at diagnosis (P value 0.529). Conclusion: Most patients included in this study had locally advanced disease stages. Menopausal status affected grade and LVI but not stage. Further professional efforts, endorsed by practical policy decisions, are recommended to down stage breast cancer through promoting evidence based protocol guidelines and adopting comprehensive well designed diagnostic, screening and cancer control strategies.

Pro-inflammatory cytokines increase temporarily after adjuvant treatment for breast cancer in postmenopausal women: a longitudinal study

BackgroundBreast cancer patients have an increased risk of cardiometabolic disease and for many patients, adjuvant therapy causes an altered lipid profile, insulin resistance and inflammation. Previous follow-up studies are inconclusive regarding the duration of therapy-induced inflammation. We examined the acute and persistent changes of adjuvant chemotherapy on inflammatory and metabolic health markers in breast cancer patients.MethodsPlasma levels of IL-6, IL-8, IL-10, IFN-γ, TNF-α, high-sensitivity C-reactive protein (hsCRP) and metabolic health parameters were analyzed before, shortly after and every six months up to two years after adjuvant chemotherapy treatment in 51 postmenopausal early breast cancer (EBC) patients, as well as in 41 healthy age- and BMI-matched controls. A target-specific multiplex assay was applied for cytokine measurements.ResultsBefore initiation of adjuvant therapy, plasma IL-8 levels were higher in EBC patients (31%, p = 0.0001). Also, a larger proportion of the patients had a hsCRP level above 2 mg/L (41%) compared to the controls (17%, Χ2 = 5.15, p = 0.023). Plasma levels of all five cytokines, but not hsCRP, were significantly increased after compared to before adjuvant chemotherapy (15–48% increase; all p ≤ 0.05). Already six months after ending chemotherapy treatment, all plasma cytokine levels were significantly reduced and close to pre-chemotherapy levels. Adjuvant chemotherapy caused a worsened lipid profile (increased triglycerides, lower HDL levels), insulin resistance and increased plasma insulin levels that remained high during the first year after chemotherapy.ConclusionPostmenopausal women with EBC have temporarily increased plasma levels of pro-inflammatory cytokines after adjuvant chemotherapy. Although transient, the therapy-induced increase in plasma cytokine levels, together with dyslipidemia and insulin resistance, may contribute to cardiometabolic risk in breast cancer patients treated with adjuvant chemotherapy.Trial registration The clinical trial (registration number NCT03784651) was registered on www.clinicaltrials.gov on 24 December 2018.

Preoperative plasma fibrinogen level is a risk factor for the long-term survival of postmenopausal women after surgery for breast cancer

BackgroundStudies have indicated an association between fibrinogen levels and the prognosis of breast cancer patients. However, fibrinogen levels are notably susceptible to fluctuations due to the menstrual cycle. This study explored the relationship between preoperative plasma fibrinogen levels and the prognosis of postmenopausal breast cancer women after surgery. Method855 patients with postmenopausal breast cancer were monitored for 10 years. Cox proportional hazards regression models were used to perform univariate and multivariate analyses to identify factors that are of substantial prognostic value. ResultsThe median follow-up was 77 months (51–105 months), and the maximum 142 months. Over the follow-up period, 65 deaths (7.6 %) were recorded. Multivariate Cox regression results show that preoperative plasma fibrinogen level (hazard ratio [HR] =1.615, 95 % confidence interval [CI]: 1.233–2.115) and age (HR = 1.626, 95%CI: 1.250–2.116) were independent risk factors for 10-year overall survival after surgery in postmenopausal breast cancer patients, while endocrine therapy (HR = 0.414, 95%CI: 0.202–0.846) was an independent protective factor. Multivariate Cox regression results also show preoperative plasma fibrinogen level was an independent risk factor for 10-year disease-free survival (HR = 1.398, 95 % CI: 1.137–1.719) and 10-year distant metastasis-free survival (HR = 1.436, 95%CI: 1.153–1.787). ConclusionElevated pretreatment plasma fibrinogen levels are associated with a poorer long-term prognosis in postmenopausal breast cancer patients following surgical treatment.

Adverse Event Profiles of the Third-Generation Aromatase Inhibitors: Analysis of Spontaneous Reports Submitted to FAERS.

The third-generation aromatase inhibitors (AIs), represented by letrozole, anastrozole, and exemestane, have been used as a standard first-line adjuvant therapy for postmenopausal breast cancer patients with positive hormone receptor. However, their safety in the real world has not been systematically analyzed. We used the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to investigate adverse event (AE) profiles of the three AIs, covering the period from Q1 2004 to Q3 2023. The time-to-event onset profiles and cumulative incidence were analyzed by Weibull shape parameter test and Kaplan-Meier method, respectively. The disproportionality analysis was utilized to assess drug toxicity risk. Based on the FAERS database, 18,035, 8242, and 7011 reports listing letrozole, anastrozole, and exemestane as primary suspected drugs were extracted, respectively. AEs associated with anastrozole displayed the latest onset (p < 0.0001); meanwhile, WSP test showed that all three AIs had early failure-type profiles. At the preferred term level, we acquired 95, 59, and 42 significant signals associated with letrozole, anastrozole, and exemestane, which involved 18, 13, and 15 system organ classes, respectively. The three AIs all reported that their strongest AE signal was trigger finger. Neutropenia was the most frequent AE for letrozole, while the highest occurrences of anastrozole and exemestane were arthralgia. We also found that interstitial lung disease, a rare but serious AE, showed strong signal intensity in all three AIs. Additionally, letrozole was also associated with lots of other rare but serious AEs in hematologic, respiratory, and hepatic systems, which were not recorded in the instructions. Our analysis of safety warning signals of the third-generation AIs from the FAERS database provided reference for clinical safe and rational drug use.

Half of most frequently mutated genes in breast cancer are expressed differentially between premenopausal and postmenopausal breast cancer patients

Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer.

A randomized trial of the impact of symptom monitoring using an electronic patient-reported outcome app on health-related quality of life in postmenopausal breast cancer patients receiving adjuvant endocrine therapy.

Electronic patient-reported outcomes (ePRO) monitoring is a useful communication tool for cancer patients and healthcare providers. In this study, we examined the impact of symptom monitoring using an ePRO app on quality of life (QoL) in postmenopausal breast cancer patients receiving adjuvant endocrine therapy. The free app "Welby My Carte ONC" was used in the study. Patients with breast cancer starting adjuvant endocrine therapy were randomly assigned in a 1:1 ratio to ePRO monitoring (ONC) and control groups. The ONC group reported five symptoms extracted from the Patient-Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE) (insomnia, joint pain, headache, anxiety, and hot flashes) weekly for 3months through the app. Reported symptoms were shared with medical personnel. When serious symptoms were reported, these personnel ascertained the patient's health status and provided advice over the phone. The primary endpoint was QoL measured by the Functional Assessment of Cancer Therapy-Breast (FACT-B) at 3months from enrollment. Differences between groups were tested using analysis of covariance. The study included 125 subjects with mean age of 64years in the ONC group (n = 61) and 63years in the control group (n = 64). In the ONC group, the response rate to PRO-CTCAE was about 70% or higher until week 10. The item missing rate was 0. The ONC group reported more symptoms related to joint pain and insomnia. The difference in FACT-B total score between the groups was -1.55 (95% confidence interval: -5.91, 2.81), indicating no significant difference. Symptom monitoring using ePRO early after initiation of adjuvant endocrine therapy after surgery did not improve QoL of breast cancer patients.

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care – The PreFace Study

AbstractAdjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy.From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5 mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed.3297 patients started letrozole therapy. The majority of patients (n = 1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95% CI: 88–90%) and five-year OS rates were 95% (95% CI: 94–96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients).The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

HEALTH-RELATED QUALITY OF LIFE IN POSTMENOPAUSAL WOMEN WITH ADVANCED BREAST CANCER RECEIVING ADJUVANT HORMONE THERAPY (RIBOCICLIB AND LETROZOLE)

Breast cancer is a type of cancer that affects many women in Indonesia. Adjuvant hormone therapies, such as letrozole and ribociclib, have succeeded in improving the patient's quality of life. This study aimed to assess the quality of life of postmenopausal women with advanced breast cancer who received adjuvant hormone therapy with ribociclib and letrozole. A cross-sectional study was conducted using retrospective data from postmenopausal female breast cancer patients at Dharmais Cancer Hospital between 2020 and 2023 who met the inclusion criteria. To determine the impact of sociodemographics on patient quality of life, data were examined using the quality of life score (EQ5D5L) and Spearman test. There were 29 patients, with a mean age of 54.9 years (SD = 8.65); the highest education level was high school (34.5%); The majority of occupations are housewives (69%), and the majority are stage IV (34.5%). The mean utility and VAS values of Ribociclib were 0.885 and 81.66, respectively, whereas those for letrozole were 0.725 and 78.46, respectively. Analysis of the relationship between quality of life and patient characteristics showed that the quality of life of patients with breast cancer treated with adjuvant ribociclib and letrozole therapy was influenced by the stage of breast cancer (p = 0.008). These findings indicate that patients receiving ribociclib and letrozole therapy have a good quality of life, which quality of life quality of life is influenced by the stage of malignancy. Keywords: breast cancer, quality of life, letrozole, ribociclib, post menopause

Abstract PO4-02-14: Parity and age first full term pregnancy affects the odds of different breast cancer subtypes defined by estrogen receptor and human epidermal growth factor receptor-2

Abstract Background: A rising trend in the incidence of estrogen receptor (ER)-positive subtype over time is observed in several high-income countries, while the incidence of ER-negative subtype is decreasing in some areas. It has been found that decreased parity and late age at 1st full-term pregnancy (FTP1) can increase the risk of breast cancer (BC). This study aims at investigating the association between two reproductive factors, parity and FTP1, and the odds of BC subtypes in premenopausal and postmenopausal patients. Patients and method: This study included patients diagnosed with early-stage BC after the age of 34, who were treated in UZ Leuven between January 2000 and November 2020. The patients were classified into four subtypes defined by ER and human epidermal growth factor receptor-2 (HER2). ER positivity was defined as &amp;gt;1% of cells staining positive while HER2 positivity was based on fluorescence in situ hybridization (FISH) testing of samples with immunohistochemistry score of 2+ or 3+. Baseline-category logit models with subtype as the response (ER+/HER2- as the baseline) and adjusted for age at diagnosis and BMI, were performed for premenopausal and postmenopausal patients separately. First, we exclude nulliparous patients. Parity (1-2 or ≥3) and FTP1 (continuous) were included in the models as the covariates of interest in the first model. To evaluate the effects of reproductive patterns compared to nulliparity, a new variable reproductive pattern was created by taking intersection of parity groups and FTP1 groups (&amp;lt; 27, ≥27). Reproductive pattern was set as the covariate of interest in the second model. Result: After imputing the missing values, we included 9606 patients in the study. 8125 of them were parous. In parous patients, high FTP1 was associated with low odds of ER-/HER2- BC relative to ER+/HER2- BC for both premenopausal and postmenopausal patients (table 1). In postmenopausal patients, low parity was associated with low odds of ER-/HER2- BC and high odds of ER+/HER2+ BC relative to ER+/HER2- BC. There was no evidence that parity affects the odds of subtypes in premenopausal patients. When investigating the effect of different reproductive patterns compared to nulliparity on the odds of subtypes, there was no evidence that reproductive patterns will affect the odds of subtypes in premenopausal patients. Postmenopausal patients who had FTP1 before 27 years old and had at least three children tended to have higher odds of ER-/HER2- BC relative to ER+/HER2- BC compared to nulliparous patients. Conclusion: In parous patients, increased FTP1 was associated with reduced odds of ER-/HER2- relative to ER+/HER2- BC. In postmenopausal patients, patients with at least three children tended to have low odds of ER-/HER2- BC and high odds of ER+/HER2+ BC relative to ER+/HER2- BC. When compared to nulliparity, the combination of having at least three children and having the first child before 27 years old increased the odds of ER-/HER2- BC relative to ER+/HER2- BC in postmenopausal patients. Table 1 Effect of FTP1, parity on subtype odds Menopause Subtype Effect Odds ratio (95%CI) p-value pre ER-/HER2- FTP1 (continuous) 0.960 (0.935, 0.985) 0.0021 post 0.969 (0.948, 0.990) 0.0047 pre ER-/HER2+ 0.992 (0.952, 1.034) 0.7166 post 1.005 (0.977, 1.034) 0.7081 pre ER+/HER2+ 0.976 (0.949, 1.004) 0.0962 post 1.015 (0.992, 1.039) 0.1969 pre ER-/HER2- Parity 1-2 vs ≥3 1.194 (0.899, 1.585) 0.2200 post 0.784 (0.648, 0.949) 0.0124 pre ER-/HER2+ 1.152 (0.723, 1.834) 0.5521 post 0.896 (0.684, 1.173) 0.4228 pre ER+/HER2+ 1.080 (0.795, 1.469) 0.6220 post 1.300 (1.022, 1.654) 0.0329 The baseline category is ER+/HER2- subtype Effect of age at first full-term pregnancy and parity on subtype odds Citation Format: Zhao Liu, Jiumeng Zhang, Karen Van Baelen, Maja Vangoitsenhoven, Hans Wildiers, Adelheid Soubry, Patrick Neven. Parity and age first full term pregnancy affects the odds of different breast cancer subtypes defined by estrogen receptor and human epidermal growth factor receptor-2 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-14.

Abstract PO1-19-04: Dalpiciclib and tucidinostat in patients with HR+/HER2- advanced breast cancer and resistance to CDK4/6 inhibitors: A phase Ib trial

Abstract Background: Hormone receptor (HR)-positive/epidermal growth factor receptor 2 (HER2)-negative breast cancer accounts for approximately 70% of all breast cancers and is associated with a better prognosis. Estrogen plays an important role in the growth of HR-positive breast cancer, thus patients with this type of tumor are sensitive to hormone inhibitors. However, a quarter of patients will inevitably relapse. Several large clinical trials have demonstrated that the combination of CDK4/6 inhibitors and endocrine therapy (ET) as first or second-line therapy could improve the progression-free survival (PFS) and overall survival for patients with breast cancer. In China, dalpiciclib (a CDK4/6 inhibitor) in combination with fulvestrant has been approved for patients with recurrent or metastatic HR-positive/HER2-negative breast cancer who have failed ET. Moreover, the combination of dalpiciclib and aromatase inhibitors (AI) as an initial treatment for patients with locally advanced or metastatic HR-positive/HER2-negative breast cancer has also been accepted. However, the standard treatment for patients who have failed CDK4/6 inhibitors has not been established. Histone deacetylase (HDAC) inhibitors cause alterations in gene expression in many signaling pathways associated with oncogenesis, leading to the arrest of tumor cell growth and differentiation, as well as promoting tumor apoptosis. Tucidinostat (an HDAC inhibitor) plus AI has been approved for the treatment of locally advanced HR-positive/HER2-negative postmenopausal breast cancer patients who have failed ET. Theoretically, synergistic effects may occur when HDAC inhibitors are combined with CDK4/6 inhibitors. Currently, the clinical data on combination therapy with CDK4/6 inhibitors and HDAC inhibitors have not been reported. Herein, our study aims to explore the efficacy and safety of dalpiciclib and tucidinostat in patients with late-stage HR+/HER2- breast cancer who have failed CDK4/6 inhibitors. Trial Design: The present study is a single-arm, open-label, phase I, dose escalation clinical trial (NCT 05586841). Patients were assigned to four groups to receive either dalpiciclib 125mg/d and tucidinostat 25mg/BIW (group A) or dalpiciclib 125mg/d and tucidinostat 20mg/BIW (group B) or dalpiciclib 100 mg/d and tucidinostat 25mg/BIW (group C) or dalpiciclib 100 mg/d and tucidinostat 20mg/BIW (group D). The Bayesian Optimal Interval (BOIN) design was performed to determine dose-escalation and de-escalation to find the maximum tolerated dose (MTD) of dalpiciclib plus tucidinostat. Key Eligibility Criteria: The study is enrolling female patients who are older than 18 years, with HR-positive/HER2-negative locally recurrent or metastatic breast cancer (MBC), with Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2. Before entering this trial, all patients must have received ≤1 previous line of chemotherapy for recurrent or MBC, and have failed CDK4/6 inhibitor therapy. Aims: The BOIN design is employed to explore the optimal dose combination of dalpiciclib and tucidinostat and determine recommended doses for a phase II dose expansion clinical trial, based on prespecified dose-limiting toxicity (DLT). Statistical Methods: Safety will be evaluated in the safety set including all patients who received at least one dose of study treatment and underwent at least one safety assessment. Efficacy will be assessed in the full analysis set, defined as all patients who received at least one dose of study treatment. Present and Planned Accrual: Up to 30 participants were planned to be enrolled in the present study. The first participant was enrolled on 18 January 2023. The recruitment is ongoing. Citation Format: Tao Wang, Jinmei Zhou, Xuexue Wu, Zefei Jiang. Dalpiciclib and tucidinostat in patients with HR+/HER2- advanced breast cancer and resistance to CDK4/6 inhibitors: A phase Ib trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-04.

Long-term effects of aromatase inhibitor withdrawal on bone mineral density in early breast cancer patients: 10-year follow-up results of the BREX study

PurposeWe aimed to provide long-term bone mineral density (BMD) data on early breast cancer patients of the BREX (Breast Cancer and Exercise) study. The effects of exercise and adjuvant endocrine treatment 10 years after randomization were analyzed, with special emphasis on aromatase inhibitor (AI) therapy discontinuation at 5 years.MethodsThe BREX study randomized 573 pre- and postmenopausal breast cancer patients into a 1-year supervised exercise program or a control group. 372 patients were included into the current follow-up analysis. BMD (g/cm2) was measured by dual-energy X-ray absorptiometry at lumbar spine (LS), left femoral neck (FN), and the total hip. Separate groups were displayed according to baseline menopausal status, and whether the patient had discontinued AI therapy at 5 years or not.ResultsThe BMD change from 5 to 10 years did not significantly differ between the two randomized arms. AI discontinuation at 5 years had statistically significant BMD effects. The FN BMD continued to decrease in patients who discontinued AI therapy during the first 5-year off-treatment, but the decrease was three-fold less than in patients without AI withdrawal (− 1.4% v. − 3.8%). The LS BMD increased (+ 2.6%) in patients with AI withdrawal during the first 5 years following treatment discontinuation, while a BMD decrease (-1.3%) was seen in patients without AI withdrawal.ConclusionThis study is to our knowledge the first to quantify the long-term impact of AI withdrawal on BMD. Bone loss associated with AI therapy seems partially reversible after stopping treatment. Trial registration: http://www.clinicaltrials.gov/ (Identifier Number NCT00639210).

Abstract 756: Differences in composition, diversity, and function of the fecal microbiota of post-menopausal breast cancer patients compared to healthy, age-matched controls

Abstract Gut microbiota are a community of organisms that colonize the intestinal tract with essential roles in immune function, gut epithelial integrity, and metabolite production. Dysbiosis occurs when the gut microbiota environment is negatively altered causing detrimental changes to these functions, which may predispose an individual to breast cancer development. To understand the relationship between dysbiosis and breast cancer development, fecal microbiota samples were collected from 27 post-menopausal breast cancer patients of varying hormone receptor statuses (ER+HER2-, ER+Her2+, ER-HER2+, or ER-Her2-) prior to starting chemotherapeutic treatment. Samples were compared to 25 healthy controls, and all samples underwent 16srRNA sequencing. Samples from breast cancer patients and control groups were compared for significant differences (P&amp;lt;.05) in alpha (within sample) and beta (between sample) diversity. Using the Shannon Index and Generalized Least Squares Model, significant differences in alpha diversity were identified between all breast cancer types vs. controls (P=.0104), and between ER+HER2- breast cancer vs. controls (P=.00153). Healthy controls exhibited a higher mean Shannon Index than breast cancer patients, thus higher within sample diversity. Using principal coordinate analyses, significant differences in beta diversity were identified between all breast cancer types vs. controls (P = .01199), and ER+HER2- breast cancer vs. control (P = .008991). Further analyses identified significant taxa of microbiota with functions related to breast cancer development and progression. Of note, Lachnoclostridium, a genus of bacteria that can produce β-glucuronidase, which can deconjugate estrogen, was increased in all breast cancer types and ER+HER2- breast cancer when compared to controls. Deconjugation of estrogen can cause elevated blood estrogen levels, potentially increasing Estrogen Receptor binding in hormone-receptor-positive breast cancer. Additionally, Akkermansia, a genus implicated in gut barrier dysfunction, was decreased in ER+HER2- patients, while Parvimonas, a tumorigenic cell-cycle regulator, was increased. Elucidating if these effects are causative or reactionary may have important implications for understanding breast cancer etiology. Samples are currently undergoing additional metagenomic analyses using long-read sequencing to identify specific bacteria, viruses, fungi, parasites, and phages that may be contributing to dysbiosis. Overall, this study is the first, to our knowledge, to employ short and long-read sequencing to the fecal samples of untreated postmenopausal breast cancer patients. We provide mechanistic insight into the relationship between microbiota and breast cancer development, with the intent of informing future patient screening and prevention. Citation Format: Nadia Kabbej, Frederick Ashby, Erika Atencio, Erinn Rosenkrantz, Dominique Day, Khloe Dang, Josee Gauthier, Rachel Newsome, John Sommerville, Taqwa Naas, Raad Gharaibeh, Christian Jobin, Amira Quevedo, Coy D. Heldermon. Differences in composition, diversity, and function of the fecal microbiota of post-menopausal breast cancer patients compared to healthy, age-matched controls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 756.

Abstract 782: Correlation between collagen peptides and physical features of fibrosis in breast tissue from women at increased risk of cancer

Abstract Breast cancer risk increases significantly in women who maintain higher radiologically dense breast tissue as they age. However, the mechanisms that underlie this association remain poorly understood, especially in postmenopausal women. A predominant contributor to dense breasts and differences between women is the relative amount of fibrillar collagens. Experimental models suggest that changes in collagen properties such as fiber alignment and stiffness promote local stromal fibrosis, which we hypothesize may contribute to the relationship between breast density, aging, and tumorigenesis. Normal breast biopsy samples from the contralateral, healthy breast of 32 postmenopausal breast cancer patients participating in a clinical trial for drug effect on breast density were examined and scored for areas of fibrosis and analyzed using second harmonic generation microscopy (SHG) and mass spectrometry proteomics. Our aim was to identify areas of fibrosis and relate the severity of focal fibrosis to the physical properties and peptide composition of collagen fibers. Using GraphPad Prism, we conducted one-way ANOVA and Kruskal-Wallis tests and post-hoc multiple comparison tests. H&amp;E-stained breast tissue samples were scored according to percent fibrosis. The minimum and maximum percent fibrosis were 5% and 100%, respectively, with a median of 60% (95% CI: 97.06%). Out of 31 people, 16 had a higher fibrosis score than the median. Consistent with pathologic scoring of the presence and extent of fibrosis, fiber counts were significantly lower in tissue with lower fibrosis scores than samples with more highly scored fibrosis (p-value &amp;lt;0.001). Distance to the nearest fiber was greater in samples with &amp;lt; 20% fibrosis, whereas greater alignment to the nearest fiber was observed in higher fibrosis percentages. At the molecular level, 22 peptides demonstrated a strong correlation with percent fibrosis (spearman r ≥ 60), of which 13 peptides were statistically significant (p-value &amp;lt;0.0001). The putatively identified peptides belong to type I, III, IV and VI collagens. Fiber length and straightness, but not fiber width, were higher in tissues with greater percent fibrosis. Significant correlations were identified between collagen physical features and peptides: two distinct peptides correlated with collagen fiber length and straightness while 20 peptides correlated with fiber width. These putative peptides belong to types I, III, IV and V collagens with ~70% of the peptides containing at least one hydroxyproline modification. This study is the first to explore the link between focal fibrosis and collagen-associated peptides in healthy breast tissue of high-risk postmenopausal women. These findings provide novel insights on stromal collagens associated with fibrotic changes in normal at-risk breast tissue that may act in tissue susceptibility to tumor formation. Citation Format: Denys Rujchanarong, Alison T. Stopeck, Christina Preece, Ren Sun, Pavani Chalasani, Sean Brown, Ji D. Bai, Heather Jensen Smith, Sungyong You, Peggi M. Angel, Patricia Thompson. Correlation between collagen peptides and physical features of fibrosis in breast tissue from women at increased risk of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 782.

Aromatase Inhibitors and Plasma Lipid Changes in Postmenopausal Women with Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Women are typically diagnosed with estrogen receptor-positive breast cancer around the postmenopausal period when declining estrogen levels initiate changes in lipid profiles. Aromatase inhibitors (AI) are used to prevent the progression of cancer; however, a further reduction in estrogen levels may have detrimental effects on lipid levels, which was our working hypothesis. Methods: Our meta-analysis was conducted on the lipid profiles of postmenopausal breast cancer patients at baseline and at different treatment time points. Results: We identified 15 studies, including 1708 patients. Studies using anastrozole (ANA), exemestane (EXE), letrozole (LET), and tamoxifen (TMX) were involved. Subgroup analyses revealed that 3- and 12-month administrations of LET and EXE lead to negative changes in lipid profiles that tend to alter the lipid profile undesirably, unlike ANA and TMX. Conclusions: Our results suggest that, despite statistically significant results, EXE and LET may not be sufficient to cause severe dyslipidemia in patients without cardiovascular comorbidities according to the AHA/ACC Guideline on the Management of Blood Cholesterol. However, the results may raise the question of monitoring the effects of AIs in patients, especially those with pre-existing cardiovascular risk factors such as dyslipidemia.

Validation of the Prognostic Performance of Breast Cancer Index in Hormone Receptor-Positive Postmenopausal Breast Cancer Patients in the TEAM Trial.

Patients with early-stage hormone receptor-positive (HR+) breast cancer face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0-10 years) and late (5-10 years) distant recurrence (DR) risk in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. 3,544 patients were included in the analysis (N = 1,519 N0, N = 2,025 N+). BCI risk groups were calculated using pre-specified cutoff points. Kaplan-Meier analyses and log-rank tests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates. For overall 10-year DR, BCI was significantly prognostic in Ni0 (N = 1,196) and N1 (N = 1,234) patients who did not receive prior chemotherapy (P < 0.001). In patients who were DR-free for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N = 1,285) and 4.8% and 12.2% (N1 cohort, N = 1,625) with multivariate HRs of 2.25 (95% CI, 1.30-3.88; P = 0.004) and 2.67 (95% CI, 1.53-4.63; P < 0.001), respectively. Late DR performance was substantially improved using previously optimized cutoff points, identifying BCI low-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively. The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ patients with early-stage breast cancer.

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

Adjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy. From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed. 3297 patients started letrozole therapy. The majority of patients (n=1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95%CI: 88-90%) and five-year OS rates were 95% (95%CI: 94-96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients). The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

Breast cancer but not the menopausal status is associated with small changes of the gut microbiota.

Possible relationships between gut dysbiosis and breast cancer (BC) development and progression have been previously reported. However, the results of these metagenomics studies are inconsistent. Our study involved 88 patients diagnosed with breast cancer and 86 cancer-free control women. Participants were divided into groups based on their menopausal status. Fecal samples were collected from 47 and 41 pre- and postmenopausal newly diagnosed breast cancer patients and 51 and 35 pre- and postmenopausal controls, respectively. In this study, we performed shotgun metagenomic analyses to compare the gut microbial community between pre- and postmenopausal BC patients and the corresponding controls. Firstly, we identified 12, 64, 158, and 455 bacterial taxa on the taxonomy level of phyla, families, genera, and species, respectively. Insignificant differences of the Shannon index and β-diversity were found at the genus and species levels between pre- and postmenopausal controls; the differences concerned only the Chao index at the species level. No differences in α-diversity indexes were found between pre- and postmenopausal BC patients, although β-diversity differed these subgroups at the genus and species levels. Consistently, only the abundance of single taxa differed between pre- and postmenopausal controls and cases, while the abundances of 14 and 23 taxa differed or tended to differ between premenopausal cases and controls, and between postmenopausal cases and controls, respectively. There were similar differences in the distribution of enterotypes. Of 460 bacterial MetaCyc pathways discovered, no pathways differentiated pre- and postmenopausal controls or BC patients, while two and one pathways differentiated cases from controls in the pre- and postmenopausal subgroups, respectively. While our findings did not reveal an association of changes in the overall microbiota composition and selected taxa with the menopausal status in cases and controls, they confirmed differences of the gut microbiota between pre- and postmenopausal BC patients and the corresponding controls. However, these differences were less extensive than those described previously.

Identification of genes and pathways associated with menopausal status in breast cancer patients using two algorithms

BackgroundMenopausal status has a known relationship with the levels of estrogen, progesterone, and other sex hormones, potentially influencing the activity of ER, PR, and many other signaling pathways involved in the initiation and progression of breast cancer. However, the differences between premenopausal and postmenopausal breast cancer patients at the molecular level are unclear.MethodsWe retrieved eight datasets from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) associated with menopausal status in breast cancer patients were identified using the MAMA and LIMMA methods. Based on these validated DEGs, we performed Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein–protein interaction (PPI) networks were constructed. We used DrugBank data to investigate which of these validated DEGs are targetable. Survival analysis was performed to explore the influence of these genes on breast cancer patient prognosis.ResultsWe identified 762 DEGs associated with menopausal status in breast cancer patients. PPI network analysis indicated that these genes are primarily involved in pathways such as the cell cycle, oocyte meiosis and progesterone-mediated oocyte maturation pathways. Notably, several genes played roles in multiple signaling pathways and were associated with patient survival. These genes were also observed to be targetable according to the DrugBank database.ConclusionWe identified DEGs associated with menopausal status in breast cancer patients. The association of these genes with several key pathways may promote understanding of the complex characterizations of breast cancer. Our findings offer valuable insights for developing new therapeutic strategies tailored to the menopausal status of breast cancer patients.

Metabolic Syndrome and Postmenopausal Breast Cancer Patients and Related Factors Study

Metabolic Syndrome and Postmenopausal Breast Cancer Patients and Related Factors Study

Association between Serum Insulin and Interleukin-6 levels with Breast Cancer in Post-Menopausal Iraqi Women

Background: Obesity rates are increasing day by day affecting all populations at different ages. The most prevalent kind of cancer among women worldwide is breast cancer, with increasing rates in the present time and in the future. Substantial connections between obesity and breast cancer are demonstrated. Elevated circulating levels of insulin and interleukin-6 have a substantial link to obesity and breast cancer development. Objective: This study aimed to examine the serum levels of insulin and interleukin-6 in postmenopausal breast cancer patients and to study the connection between these biomarkers and breast cancer development. Method: In this research, 120 postmenopausal women actively participated., 30 had a body mass index of &gt;30kg/m2 diagnosed with breast cancer and considered as obese (group 1), 30 with a body mass index of &lt;30kg/m2 with breast cancer and considered as not obese (group 2), 30 had a body mass index of &gt;30 kg/m2 who were apparently healthy and were obese (group 3), and 30 participants with a body mass index of &lt;30 kg/m2 , were apparently healthy and were not obese (group 4). Five millilitres of venous blood were provided by each individual. Insulin and interleukin-6 levels in the blood were measured using ELISA (enzyme-linked immunosorbent assay) kits. Results: Serum insulin levels were higher in the groups of obese participants (groups 1 and 3) than the groups of non-obese participants (groups 2 and 4), serum levels of interleukin-6 were the lowest in the healthy control group without obesity (group 4). Substantial moderate correlation was found between body mass index and both insulin and interleukin-6. Postmenopausal breast cancer risk is increased with elevations of serum insulin and interleukin-6. Conclusions: Elevated levels of serum interleukin-6 and insulin were linked to higher body mass index. In addition, in addition interleukin-6 elevated levels were linked to the cancer state of the non-obese patients. Risk of breast cancer increased with higher levels of circulating insulin and intereukin-6. Received: Mar,, 2023 Accepted: May, 2023 Published: Jan.2023