Cancer In Postmenopausal Women Research Articles

In silico Approach and Molecular Docking Studies of Potent Bioactive Compounds of Carica papaya as Anti-breast Cancer Agents.

Breast cancer is one of the greatest global dilemmas, and the current treatment option is to target hormone receptors with partial agonists/antagonists. Estrogen and aromatase enzymes play important roles in breast cancer. Excessive estrogen activity or inadequate estrogen production leads to various hormonal issues, including breast cancer. Potent breast cancer drugs are Tamoxifen, Paclitaxel, Cyclophosphamide, Trastuzumab, etc., and aromatase inhibitors, include Anastrozole, Letrozole, and Exemestane, etc. In general, breast cancer drugs cause numerous adverse effects in humans. This study has attempted to identify alternative drug candidates from Carica papaya for treating breast cancer with fewer side effects. To achieve this, we have utilized computational methods to predict the characteristics of bioactive compounds from Carica papaya and determine the target binding affinities using the Schrödinger suite (Maestro 9.5). The target protein and ligands were obtained from the well-known database. Carica papaya has 35 identified bioactive compounds that were drawn using ChemDraw software and performed Ligand preparation wizard. Absorption, Distribution, Metabolism, and Excretion (ADME) analysis is performed with QikProp. From the docking studies, the phytocompounds such as Chlorogenic acid, Myricetin, Quercetin, Isorhamnetin, and Catechin showed the highest Glide scores (G Score). Among the five bioactive phytocompounds, Chlorogenic acid has a higher G Score with good binding energy than Tamoxifen, Anastrozole, and Letrozole standards. The pharmacokinetic properties and drug-likeness of phytocompounds were determined using ADME profiling. Carica papaya phytocompounds serve as an antiestrogen or aromatase inhibitor that regulates estrogen levels to reduce the risk of breast cancer in postmenopausal women. As a result, we recommend that these top five bioactive phytocompounds be investigated further in in vitro and in vivo studies.

Is BMD (Bone Mineral Density) a prognostic factor for luminal A breast cancer in postmenopausal women?

e12542 Background: There are some studies concerned about the relationship of BMD (Bone Mineral Density) and breast cancer risks in menopausal women. However, most studies have limitations in that they did not distinguish the subtypes of breast cancer. Therefore, we assessed the BMD as a risk factor of recurrences, metastases, or occurrences of contralateral breast cancer in the luminal A breast cancer patients with menopause. Methods: In this retrospective study, the data of 348 luminal A type breast cancer patients, who underwent treatment at the Pusan National University Yangsan Hospital from 2012 to 2016, were analyzed. BMD of the lumbar spine, total femur, and femoral neck was measured by Dual Energy X-ray Absorptiometry (DXA). According to the measured BMD and WHO criteria, the group with T scores ≥ -1.0 was defined as normal, the group with T scores < -1.0 and > -2.5 was defined as osteopenia, and the group with T scores < -2.5 was defined as osteoporosis. The patients were divided into two groups: those with normal BMD and those with low BMD including osteopenia or osteoporosis in preoperative examination. We also divided patients as three groups: one group with no change of BMD, the other group with improvement of BMD and the other with deterioration of BMD during treatment. We used Chi-squared tests, Kaplan-Meier method and Cox-regression model to analyze the relationship between BMD and breast cancer risk. Results: Among the 348 patients, normal BMD was confirmed by preoperative examination in 129 patients and low BMD was identified in 219 patients. There was no change in BMD during the treatment in 243 patients. The improvement in BMD was identified in 37 patients, and the deterioration of BMD was confirmed in 68 patients. Younger patients were distributed in normal BMD compared to low BMD (55.7±6.9 vs 61.8±8.0, p<0.05). There were only 14 patients (4.0%) with recurrences, distant metastases or occurrences of contralateral breast cancer during a median follow-up period of 78 months. Among the 219 patients with low BMD, disease-free survival at 5 years was 98.2% compared to 95.0% for 129 patients with normal BMD ( p=0.326). In addition, disease-free survival at 5-years was 97.0% in no change of BMD during treatment, 94.6% in improvement of BMD, and 98.4% in deterioration of BMD ( p=0.785). Conclusions: In this study, BMD did not have statistically significance in the recurrences, metastases, or occurrences of contralateral breast cancer in luminal A breast cancer patients with menopause. In addition, there was no statistically importance in relationship between BMD change during treatment and recurrences, metastases, or occurrences of contralateral breast cancer. Therefore, we should perform treatments to breast cancer patients preventing decreased BMD.

Telehealth delivered Tai Chi intervention for managing aromatase inhibitor-induced arthralgia in breast cancer patients: TaiChi4Joint during the COVID-19 pandemic a Pilot study.

e12523 Background: Estrogen receptor positive breast cancer (BC) is the most common type of breast cancer in postmenopausal women and aromatase inhibitors (AI) are the endocrine therapy of choice recommended for these patients. Up to 50% of those treated with an AI develop Arthralgia often resulting in poor adherence and decreased quality of life. Methods: This is a single arm longitudinal pilot study aiming to evaluate the safety, feasibility, acceptability and potential efficacy of TaiChi4Joint, a remotely-delivered 12-week Tai Chi intervention designed for the relief of AI-induced joint pain. Women diagnosed with stage 0-III BC who have been receiving an AI for at least 2 months and reporting arthralgia with a ≥ 4 score on a 0-10 scale for joint pain were eligible for study enrollment. Participants were encouraged to join Tai Chi classes delivered over ZOOM three times a week for 12 weeks. Program engagement strategies include the use of a private Facebook study group and box.com cloud for archiving live class recordings. The program utilizes Text messaging and emails with periodic positive quotes and evidence based information on Tai Chi for facilitating community bonding and class attendance. Participants were invited to complete the following assessments online at baseline, 1, 2 and 3 months intervals from study enrollment: Brief Pain Inventory (BPI), Western Ontario and McMaster University Osteoarthritis index (WOMAC), The Australian Canadian Osteoarthritis Hand Index (AUSCAN), Fatigue Symptom Inventory (FSI), Hot Flash Related Daily Interference Scale (HFRDIS), Pittsburg Sleep Quality Index (PSQI) and Center for Epidemiological Studies Depression (CES-D). Results: 55 eligible patients were invited to participate and 39 consented and completed the baseline assessments. 61% (median) Participants attended the classes, with no Tai Chi related adverse events reported. 22 of the 39 participants completed the 3-month follow up assessments with a 56% retention rate. Study participants reported improvement from baseline compared to 3 month as follows: For BPI ( P = .000), AUSCAN pain subscale ( P =.000), AUSCAN function subscale for 35 patients ( P = .000), WOMAC ( P = .000), CES-D ( P = 0.001), FSI ( P = 0.00) and PSQI ( P = .000). However HFRDIS improved in 11 patients ( P = 0.00) for the other 22 patients (P = 0.154). Conclusions: The COVID-19 global pandemic has resulted in the need to rethink how mind-body therapies can be delivered. This study demonstrated the feasibility, acceptability, and potential efficacy of a Telehealth based Tai Chi intervention for reducing AI-induced arthralgia. The intervention decreased patient reported pain, stiffness and improved sleep quality and depressive symptoms. With our promising findings, larger telehealth based trials of Tai Chi for AI-associated arthralgia are needed. Clinical trial information: NCT04716920.

Association Between Sugar-Sweetened Beverage Intake and Liver Cancer Risk in the Women’s Health Initiative

ObjectivesIntake of sugar-sweetened beverage (SSB), a postulated risk factor for obesity, diabetes, and cardiovascular disease, may drive insulin resistance and inflammation which are strongly implicated in liver carcinogenesis. However, evidence on the association between SSB intake and liver cancer is scarce. We hypothesized that higher SSB intake would be associated with a greater risk of liver cancer. MethodsWe included 90,504 women aged 50–79 years from the Women’s Health Initiative Observational Study and Clinical Trials excluding Dietary Modification Trial participants. SSB intake was defined as the sum of soft drinks and fruit drinks (1 serving = one 12 fl. oz can or 355 ml), which was assessed by a validated food frequency questionnaire administered at baseline between 1993 and 1998. Incident liver cancers were reported by self-administered questionnaires and further confirmed by medical record review. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age, race and ethnicity, education, alcohol intake, smoking status, body mass index, non-steroidal anti-inflammatory drug use, physical activity, total caloric intake, and history of diabetes. ResultsAfter a median of 18.7 years follow-up, 205 women had confirmed liver cancer. Approximately 7.3% of women consumed ≥ 1 serving/day of SSB. Higher SSB intake was associated with a 78% greater risk of liver cancer (HR ≥1/day vs never to < 3/month = 1.78, 95%CI = 1.09–2.95, P linear trend = 0.007) as compared to intake of < 3 servings/month. Non-statistically significant positive associations with liver cancer were observed for fruit drinks (HR ≥1/day vs never to < 3/month = 1.55, 95%CI = 0.88–2.75) and soft drinks (HR ≥1/day vs never to < 3/month = 1.73, 95%CI = 0.76–3.94). Results were similar after further adjustment for coffee/tea intake, or history of liver diseases, or when liver cancer cases diagnosed within the first 2 years of follow-up or those with history of diabetes were excluded. ConclusionsOur findings suggest SSB as a potential modifiable risk factor for liver cancer in postmenopausal women. Studies in men and diverse populations are needed to examine these associations more comprehensively. Funding SourcesThe WHI study is funded by the National Institute of Health.

Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds.

Drinking Water Disinfection Byproducts, Ingested Nitrate, and Risk of Endometrial Cancer in Postmenopausal Women.

Background:Disinfection byproducts (DBPs) and N-nitroso compounds (NOC), formed endogenously after nitrate ingestion, are suspected endometrial carcinogens, but epidemiological studies are limited.Objectives:We investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort.Methods:Among postmenopausal women in the Iowa Women’s Health Study cohort, we evaluated two major classes of DBPs, total trihalomethanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen () in public water supplies (PWS) in relation to incident primary endometrial cancer (1986–2014). For women using their PWS at enrollment (; ), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level (; TTHM; HAA5; ). Dietary nitrate/nitrite intakes were estimated from a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) via Cox models adjusted for age, endometrial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for . We evaluated associations for low-grade () vs. high-grade () type I tumors. We assessed interactions between exposures and endometrial cancer risk factors and dietary factors influencing NOC formation.Results:Higher average concentrations of DBPs (95th percentile: TTHM , HAA5 ) were associated with endometrial cancer risk (TTHM: , 95% CI: 1.41, 3.40; HAA5: , 95% CI: 1.19, 2.83; ). Associations were similarly observed for women greater than median years of PWS use with levels , in comparison with zero years (TTHM: , 95% CI: 1.18, 2.21; HAA5: , 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: , 95% CI: 1.17, 3.83; ) than for high-grade tumors (TTHM: , 95% CI: 0.80, 2.44; ), but differences were not statistically significant (). Associations with TTHM were stronger among ever HRT users than non-HRT users (). We observed no associations with in drinking water or diet.Discussion:We report novel associations between the highest DBP levels and endometrial cancer for our Iowa cohort that warrant future evaluation. https://doi.org/10.1289/EHP10207

Mechanistic Effects of Estrogens on Breast Cancer.

Current concepts regarding estrogen and its mechanistic effects on breast cancer in women are evolving. This article reviews studies that address estrogen-mediated breast cancer development, the prevalence of occult tumors at autopsy, and the natural history of breast cancer as predicted by a newly developed tumor kinetic model. This article reviews previously published studies from the authors and articles pertinent to the data presented. We discuss the concepts of adaptive hypersensitivity that develops in response to long-term deprivation of estrogen and results in both increased cell proliferation and apoptosis. The effects of menopausal hormonal therapy on breast cancer in postmenopausal women are interpreted based on the tumor kinetic model. Studies of the administration of a tissue selective estrogen complex in vitro, in vivo, and in patients are described. We review the various clinical studies of breast cancer prevention with selective estrogen receptor modulators and aromatase inhibitors. Finally, the effects of the underlying risk of breast cancer on the effects of menopausal hormone therapy are outlined. The overall intent of this review is to present data supporting recent concepts, discuss pertinent literature, and critically examine areas of controversy.

Triazoles Synthesis &amp; Applications as Nonsteroidal Aromatase Inhibitors for Hormone-Dependent Breast Cancer Treatment

In the last few years, nonsteroidal aromatase inhibitors (AIs) have been emerged as promising agents for treating hormone-dependent breast cancer in postmenopausal women because of their inhibitory effect on estrogen synthesis. Indeed, these compounds can block the activity of aromatase, the enzyme that intervenes in the last steps of estrogen production pathway. Triazoles are the core structures of nonsteroidal AIs. The nitrogen atom of the triazole moiety plays a fundamental role in the aromatase functionality by interacting with the iron ions of the heme group. In general, AIs possess numerous advantages as they quench the last step of estrogen synthesis without any inhibitory effects on the production of other steroids produced via the same pathway. Some AIs as anastrozole, letrozole, and vorozole have already been approved by the Food and Drug Administration in the treatment of breast cancer. The previously mentioned compounds present severe and adverse effects as polycystic ovary syndrome (PCOS), resistance onset on long-term treatments, and a higher risk of bone fractures. This review focuses intensively on the role of AIs in the treatment of hormone-sensitive types of cancers, especially the role of triazoles as nonsteroidal AIs. Also, the review provides an overview about the chemistry of triazoles along with the different methods by which the v -triazoles and s-triazoles are synthesized.

Association of a Healthy Lifestyle Index with Risk of Breast Cancer among Women with Normal Body Mass Index in the UK Biobank.

A high healthy lifestyle index (HLI), a composite score based on good diet quality, low alcohol consumption, no smoking, moderate to high physical activity, and waist circumference <80 cm, has been consistently associated with a reduced risk of breast cancer. Recently, high levels of body fat were found to be associated with an elevated risk of breast cancer in postmenopausal women with a normal body mass index (BMI; 18.5-<25 kg/m2). Whether the HLI is associated with breast cancer risk in women with normal BMI is unknown. We studied 102,572 women aged 40 to 69 years with a normal BMI at enrollment into the UK Biobank cohort study. The HLI was created by assigning to each component higher scores for healthier behaviors and then summing the scores. The HLI was categorized by tertiles and age- and multivariable-adjusted HRs for the association of the HLI with breast cancer risk by menopausal status were estimated using Cox proportional hazards models. In postmenopausal women, compared with a low HLI, higher scores were associated with a reduced risk of breast cancer [HRHLI-3rd tertile = 0.76; 95% confidence interval (CI), 0.64-0.91]. Findings were similar for premenopausal women, although they did not reach statistical significance, except when smoking status was excluded from the HLI score (HLIwithout smoking: HR3rd tertile = 0.71; 95% CI, 0.56-0.90). In normal BMI postmenopausal women, a high HLI score was associated with a reduced risk of breast cancer. Following a healthy lifestyle may reduce the risk of breast cancer among normal weight postmenopausal women.

Therapeutic Options for the Management of Aromatase Inhibitor- Associated Bone Loss.

Breast cancer is the most commonly occurring cancer in women worldwide. Early breast cancer is a kind of invasive neoplasm that has not proliferated beyond the breast or the axillary lymph nodes. Current therapeutic strategies for breast cancer mainly include local therapies such as surgery or radiotherapy and systemic therapies like chemotherapy, endocrine, and targeted therapy. Nowadays, the adjuvant treatment for hormone receptor-positive early breast cancer in postmenopausal women remains the main effective systemic therapy which can improve disease- free survival and overall survival; it involves several endocrine treatment regimens, including Selective Estrogen Receptor Modulators (SERMs), Aromatase Inhibitors (AIs), or a combination of them. AIs have been shown to be more effective in preventing recurrence in postmenopausal women with early breast cancer when compared with tamoxifen, thus representing the standard of care for adjuvant endocrine therapy. Although AIs are usually well-tolerated, they can have some side effects. Apart from the appearance of arthralgias or myalgias and cardiovascular events, AI therapies, reducing already low endogenous postmenopausal estradiol levels, cause increased bone loss and increase fracture risk in postmenopausal women. The objective of this review is to evaluate the therapeutic options in the management of Aromatase Inhibitor-Associated Bone Loss (AIBL). We reviewed the current literature dealing with different therapeutic options in the treatment of AIBL. Clinical practice guidelines recommend a careful evaluation of skeletal health in all women with breast cancer before AI therapy initiation. Adequate calcium and vitamin D intake have also been suggested. Pharmacological attempts to minimize AI-related bone loss have focused on the use of antiresorptive agents, such as bisphosphonates and denosumab to protect bone integrity and reduce the risk of fractures. Furthermore, clinical trials have shown that by making the bone microenvironment less susceptible to breast cancer metastasis, these drugs are able to increase disease- free survival. AI, that are the pillar of the systemic treatment for patients with hormone receptorpositive breast cancer, are associated with different side effects, and in particular, osteoporosis and fractures. Both bisphosphonates and denosumab are able to prevent this negative effect.

Gel-Based Proteomic Identification of Suprabasin as a Potential New Candidate Biomarker in Endometrial Cancer.

Endometrial cancer (EC) is the most frequent gynaecologic cancer in postmenopausal women. We used 2D-DIGE and mass spectrometry to identify candidate biomarkers in endometrial cancer, analysing the serum protein contents of 10 patients versus 10 control subjects. Using gel-based proteomics, we identified 24 candidate biomarkers, considering only spots with a fold change in volume percentage ≥ 1.5 or intensity change ≤ 0.6, which were significantly different between cases and controls (p < 0.05). We used Western blotting analysis both in the serum and tissue of 43 patients for data validation. Among the identified proteins, we selected Suprabasin (SBSN), an oncogene previously associated with poor prognosis in different cancers. SBSN principal isoforms were subjected to Western blotting analysis in serum and surgery-excised tissue: both isoforms were downregulated in the tissue. However, in serum, isoform 1 was upregulated, while isoform 2 was downregulated. Data-mining on the TCGA and GTEx projects, using the GEPIA2.0 interface, indicated a diminished SBSN expression in the Uterine Corpus Endometrial Cancer (UCEC) database compared to normal tissue, confirming proteomic results. These results suggest that SBSN, specifically isoform 2, in tissue or serum, could be a potential novel biomarker in endometrial cancer.

Simultaneous Method Development and Validation of Anastrozole Along with Piperine: Degradation Studies and Degradants Characterization Using LC-QTOF-ESI-MS Along with In-silico ADMET Predictions.

Anastrozole (ATZ) is a selective non-steroidal inhibitor widely used for the treatment of breast cancer in post-menopausal women. ATZ exerts its biological activity by inhibiting the enzyme aromatase, which is responsible for converting androgens to estrogens. Piperine (PIP), a natural alkaloid and the main component of black pepper, is used as a bioenhancer and for combating a variety of health issues ranging from upset stomach to dental problems. ATZ has been reported to have poor water solubility and less bioavailability. The novel combination of ATZ and PIP was proposed to enhance the bioavailability of both the compounds. However, there are no reported studies on the simultaneous estimation of ATZ and PIP as well as stability studies to explore their potential interactions and degradation profiling. A simple, accurate, precise, robust, sensitive, reliable, and economic analytical method for the simultaneous estimation of ATZ and PIP was developed using acetonitrile and water (60:40) as the mobile phase. Forced degradation studies and characterization of degradants were performed, and degradants were identified for molecular weight using LC-QTOF-ESI-MS; the structures of degradants were confirmed with mass accuracy measurements. The mechanism of each degradant has also been described in more detail in the manuscript. A total of fourteen degradants were characterized and reported for their good human oral absorption. A precise, robust, accurate, cheap, and sensitive RP-HPLC-DAD simultaneous method for the estimation of ATZ and PIP has been developed. From the future point of view, there is huge scope to conduct pharmacological, pharmacodynamic, and drug-herb interaction studies based on this fruitful outcome. All the degradants may be screened against MDR-resistant breast cancer in the future to check their potential as a drug target.

Maximum and Time-Dependent Body Mass Index and Breast Cancer Incidence Among Postmenopausal Women in the Black Women's Health Study.

While excess weight is an established risk factor for postmenopausal breast cancer, consideration of maximum body mass index (maxBMI; BMI is calculated as weight (kg)/height (m)2) or BMI at a point in time relevant for breast carcinogenesis may offer new insights. We prospectively evaluated maxBMI and time-dependent BMI in relation to breast cancer incidence among 31,028 postmenopausal women in the Black Women's Health Study. During 1995-2015, a total of 1,384 diagnoses occurred, including 787 estrogen-receptor (ER)-positive (ER+) cases and 310 ER-negative (ER-) cases. BMI was assessed at baseline and 2, 4, 6, and 8 years before diagnosis. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with women with BMI <25, those with BMI ≥35 had increased risk of ER+ breast cancer but not ER- breast cancer. For BMI assessed 2 years before diagnosis, the HRs for ER+ breast cancer associated with maxBMI ≥35 and time-dependent BMI ≥35 were 1.42 (95% confidence interval (CI): 1.10, 1.84) and 1.63 (95% CI: 1.25, 2.13), respectively. The corresponding HR for time-dependent BMI assessed 6 years before diagnosis was 1.95 (95% CI: 1.45, 2.62). These findings suggest strong associations of BMI with risk of ER+ breast cancer in postmenopausal women, regardless of timing of BMI assessment.

Aromatase inhibitor-associated musculoskeletal pain: An overview of pathophysiology and treatment modalities.

Since their introduction into clinical use in the 1970s, aromatase inhibitors have been a cornerstone of therapy for estrogen-receptor positive breast cancer in postmenopausal women. Unfortunately, this therapy leads to estrogen depletion in the body, which can lead to unpleasant side effects such as menopausal symptoms like hot flashes, insomnia, slightly increased risk of ischemic heart disease, accelerated bone loss leading to higher osteoporosis risk, and most significantly, arthralgias. The joint pain induced by aromatase inhibitor therapy is frequently cited as the leading cause of premature discontinuation; approximately 50% of patients will report new onset or worsening joint pain 1 year after therapy initiation, approximately 30% of patients discontinue therapy after 1 year, and only 50%–68% of patients remain fully compliant with therapy after 3 years. This article will describe risk factors for aromatase inhibitor–associated musculoskeletal syndrome, including genetic predispositions correlated with an increased risk of this syndrome, explain the currently understood pathophysiology, and give an overview of effective treatment options in managing this syndrome.

Recreational Physical Activity, Sitting, and Androgen Metabolism among Postmenopausal Women in the Women's Health Initiative Observational Study

Prolonged sitting and physical inactivity are associated with higher circulating levels of estrogens. It is unknown whether these risk factors are associated with circulating androgens/androgen metabolites, another set of hormones implicated in the etiology of cancers in postmenopausal women. We conducted a cross-sectional analysis of 1,782 postmenopausal women in the Women's Health Initiative Observational Study. Serum concentrations of 12 androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting time were self-reported at baseline. We performed linear regression to estimate geometric means (GM) of androgen/androgen metabolite concentrations (pmol/L) according to physical activity and sitting time, adjusting for potential confounders and stratified by menopausal hormone therapy (MHT) use. Physical activity (≥15 vs. 0 MET-h/wk) was inversely associated with estrogen-to-androgen ratios among never/former MHT users (adj-GM = 37.5 vs. 49.6 unconjugated estrone:androstenedione; 20.2 vs. 30.3 unconjugated estradiol:testosterone; all P trend ≤ 0.03) but was not associated among current MHT users. Prolonged sitting (≥10 vs. ≤5 h/d) was positively associated with these ratios among both never/former (adj-GM = 44.2 vs. 38.3, P trend = 0.10; adj-GM = 23.4 vs. 20.2, P trend = 0.17; respectively) and current MHT users (adj-GM = 197 vs. 147; 105 vs. 75.5; respectively; all P trend ≤0.02), but the associations were statistically significant among current MHT users only. The associations persisted after adjustment for BMI. After adjustment for adrenal androgens, physical activity and sitting were not associated with androgen metabolites. Physical activity and sitting were associated with serum estrogen-to-androgen ratios but not androgen metabolites. This study contributes to our understanding of the link between physical activity, sitting, and cancer risk in postmenopausal women.

An Updated Systematic Review and Meta-Analysis on Association of Serum Lipid Profile With Risk of Breast Cancer Incidence.

This meta-analysis was performed to investigate the effect of serum lipids on the risk of breast cancer incidence. PubMed, Web of Science, Scopus, and EMBASE were searched systematically from January 1998 to April 2019. Inclusion criteria were English observational studies (cohort or case-control) and the concentration of at least one of the lipid profile components (total cholesterol/triglycerides/low-density lipoprotein cholesterol/high-density lipoprotein cholesterol) measured before a diagnosis of breast cancer (BC). The studies were included in which the relative risk (RR) had been reported with 95% confidence intervals (CIs). A random-effects model was used. A total of 25 studies were found, including 2,882,789 participants in cohort studies with 45,481 cases with BC, and 1983 BC cases and 2963 case-control studies. Combined RR of cohort studies for the highest versus lowest for the BC was LDL-C: 0.95 (95% CI: 0.89-1.01), triglycerides (TG): 0.95 (95% CI: 0.91-0.99; P = 0.02), total cholesterol (TC): 0.98 (95% CI: 0.91-1.05), and HDL-C: 0.86 (95% CI: 0.63-1.18). Combined RR of case-control studies for the highest versus lowest was LDL-C: 1.08 (95% CI: 0.78-1.48), TG: 1.73 (95% CI: 0.94-3.18), TC: 1.02 (95% CI: 0.80-1.29), and HDL-C: 0.79 (95% CI: 0.65-0.97). Based on the results, it can be concluded that only TG but not TC and/or LDL-C had a significant inverse association with the risk of BC incidence. HDL-C showed a significant protective effect against breast cancer in postmenopausal women and case-control studies.

Anastrozole Loaded Nanostructured Lipid Carriers : Preparation and Evaluation

Anastrozole (ANZ) is considered constitute of the fourth –generation of Non–steroidal aromatase blockage, ANZ has use for hormone receptor positive breast cancer in postmenopausal women. The serious side effects of ANZ including, vaginal dryness, hot flashes, irritability, breast tenderness and un–stability in circulation.&#x0D; Nanostructured lipid carriers (NLCs) have recently emerged as a multifunctional platform for drug delivery in cancer therapy.&#x0D; Five formula were composed of (200 mg of glyceryl monostearate, 40 mg of oleic acid , 1% (w/w) Tween 80, 1% (w/w) Poloxamer 407, 1% (w/w) soy lecithin and Vitamin E Polyethylene Glycol Succinate.&#x0D; The mean particle size, polydispersity index, zeta potential, entrapment efficiency, loading capacity range of optimum formula F05 (166±3.86 nm), (0.271±0.04), (–23.7±2.65 mV), (42.43±3.90%) and (1.23±0.35%) respectively that prepared by same above composition but higher amplitude value (70%). The in–vitro drug leakage study demonstrated intact formula through 5 hours, with an approximately 78.37% of the drug was encapsulated, that exhibit an anomalous release mechanism.

Adipocyte-derived exosomes may promote breast cancer progression in type 2 diabetes.

Obesity and metabolic diseases, such as insulin resistance and type 2 diabetes (T2D), are associated with metastatic breast cancer in postmenopausal women. Here, we investigated the critical cellular and molecular factors behind this link. We found that primary human adipocytes shed extracellular vesicles, specifically exosomes, that induced the expression of genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem–like cell (CSC) traits in cocultured breast cancer cell lines. Transcription of these genes was further increased in cells exposed to exosomes shed from T2D patient–derived adipocytes or insulin-resistant adipocytes and required the epigenetic reader proteins BRD2 and BRD4 in recipient cells. The thrombospondin family protein TSP5, which is associated with cancer, was more abundant in exosomes from T2D or insulin-resistant adipocytes and partially contributed to EMT in recipient cells. Bioinformatic analysis of breast cancer patient tissue showed that greater coexpression of COMP (which encodes TSP5) and BRD2 or BRD3 correlated with poorer prognosis, specifically decreased distant metastasis–free survival. Our findings reveal a mechanism of exosome-mediated cross-talk between metabolically abnormal adipocytes and breast cancer cells that may promote tumor aggressiveness in patients with T2D.

Occupational exposure to organic solvents and breast cancer risk: a systematic review and meta-analysis.

Breast cancer is the most common cancer worldwide. Recent studies suggest that organic solvent exposure could be closely related to breast cancer, although the evidence remains controversial. Thus, we evaluated existing epidemiological evidence for the association between occupational solvent exposure and breast cancer. PubMed, Embase, and Cochrane Library were searched to identify published case-control and cohort studies that addressed occupational exposure to organic solvents and breast cancer, up to April, 2021. Meta-analyses using random-effects models were conducted to obtain the pooled odds ratios (OR) and 95% confidence intervals (CI) on the incidence of breast cancer in relation to occupational exposure. The pooled OR of breast cancer among workers exposed to organic solvents overall was 1.18 (95%CI, 1.11 ~ 1.25; I2 = 76.3%; 24 studies), compared to those with no exposure. After stratification by menopause and study location, it was revealed that the association between occupational exposure to organic solvents and the risk of breast cancer in postmenopausal women (OR, 1.35; 95% CI, 1.09 ~ 1.67; I2 = 73.4%; 7 studies) was significant, and there was also a clear association in workers in Europe (OR, 1.21; 95% CI, 1.12 ~ 1.32; I2 = 82.9%; 13 studies). We observed a significant association between occupational exposure to organic solvents and breast cancer in both cohort and case-control studies.

IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women

Window studies are gaining traction to assess (molecular) changes in short timeframes. Decreased tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine therapy for breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women. Nonetheless, the marker is being used on this subpopulation. We compared pathologist assessed IHC-based Ki67 in samples from pre- and postmenopausal women in a neo-adjuvant, endocrine therapy focused trial (NCT00738777), randomized between tamoxifen, anastrozole, or fulvestrant. These results were compared with (1) IHC-based Ki67 scoring by AI, (2) mitotic figures, (3) mRNA-based Ki67, (4) five independent gene expression signatures capturing proliferation, and (5) blood levels for tamoxifen and its metabolites as well as estradiol. Upon tamoxifen, IHC-based Ki67 levels were decreased in both pre- and postmenopausal breast cancer patients, which was confirmed using mRNA-based cell proliferation markers. The magnitude of decrease of Ki67 IHC was smaller in pre- versus postmenopausal women. We found a direct relationship between post-treatment estradiol levels and the magnitude of the Ki67 decrease in tumors. These data suggest IHC-based Ki67 may be an appropriate biomarker for tamoxifen response in premenopausal breast cancer patients, but anti-proliferative effect size depends on estradiol levels.