Limbic Neurons Shape Sex Recognition and Social Behavior in Sexually Naive Males.

Sexually naive animals have to distinguish between the sexes because they show species-typical interactions with males and females without meaningful prior experience. However, central neural pathways in naive mammals that recognize sex of other individuals remain poorly characterized. We examined the role of the principal component of the bed nucleus of stria terminalis (BNSTpr), a limbic center, in social interactions in mice. We find that activity of aromatase-expressing BNSTpr (AB) neurons appears to encode sex of other animals and subsequent displays of mating in sexually naive males. Silencing these neurons in males eliminates preference for female pheromones and abrogates mating success, whereas activating them even transiently promotes male-male mating. Surprisingly, female AB neurons do not appear to control sex recognition, mating, or maternal aggression. In summary, AB neurons represent sex of other animals and govern ensuing social behaviors in sexually naive males.

Neural Control of Sexually Dimorphic Social Behavior: Connecting Development to Adulthood.

Rapid advances in the neural control of social behavior highlight the role of interconnected nodes engaged in differential information processing to generate behavior. Many innate social behaviors are essential to reproductive fitness and therefore fundamentally different in males and females. Programming these differences occurs early in development in mammals, following gonadal differentiation and copious androgen production by the fetal testis during a critical period. Early-life programming of social behavior and its adult manifestation are separate but yoked processes, yet how they are linked is unknown. This review seeks to highlight that gap by identifying four core mechanisms (epigenetics, cell death, circuit formation, and adult hormonal modulation) that could connect developmental changes to the adult behaviors of mating and aggression. We further propose that a unique social behavior, adolescent play, bridges the preweaning to the postpubertal brain by engaging the same neural networks underpinning adult reproductive and aggressive behaviors.

An unusual aromatase/cyclase programs the formation of the phenyldimethylanthrone framework in anthrabenzoxocinones and fasamycin.

Aromatic polyketides are renowned for their wide-ranging pharmaceutical activities. Their structural diversity is mainly produced via modification of limited types of basic frameworks. In this study, we characterized the biosynthesis of a unique basic aromatic framework, phenyldimethylanthrone (PDA) found in (+)/(-)-anthrabenzoxocinones (ABXs) and fasamycin (FAS). Its biosynthesis employs a methyltransferase (Abx(+)M/Abx(-)M/FasT) and an unusual TcmI-like aromatase/cyclase (ARO/CYC, Abx(+)D/Abx(-)D/FasL) as well as a nonessential helper ARO/CYC (Abx(+)C/Abx(-)C/FasD) to catalyze the aromatization/cyclization of polyketide chain, leading to the formation of all four aromatic rings of the PDA framework, including the C9 to C14 ring and a rare angular benzene ring. Biochemical and structural analysis of Abx(+)D reveals a unique loop region, giving rise to its distinct acyl carrier protein-dependent specificity compared to other conventional TcmI-type ARO/CYCs, all of which impose on free molecules. Mutagenic analysis discloses critical residues of Abx(+)D for its catalytic activity and indicates that the size and shape of its interior pocket determine the orientation of aromatization/cyclization. This study unveils the tetracyclic and non-TcmN type C9 to C14 ARO/CYC, significantly expanding our cognition of ARO/CYCs and the biosynthesis of aromatic polyketide framework.

Excess body weight and postmenopausal breast cancer: Emerging molecular mechanisms and perspectives.

Postmenopausal, obese women have a significantly higher risk of developing estrogen receptor-positive (ER+) breast tumors, that are resistant to therapies and are associated with higher recurrence and death rates. The global prevalence of overweight/obese women has reached alarming proportions and with postmenopausal ER+ breast carcinoma (BC) having the highest incidence among the three obesity-related cancers in females (i.e., breast, endometrial and ovarian), this is of significant concern. Elucidation of the precise molecular mechanisms underlying the pro-cancerous action of obesity in ER+BC is therefore critical for disease prevention and novel treatment initiatives. Interestingly, accumulating data has shown opposing relationships between obesity and cancer in either pre- or post-menopausal women. Excess body weight is associated with an increased risk of breast cancer in postmenopausal women and a decreased risk in pre-menopausal women. Moreover, excess adiposity during early life appears to be protective against postmenopausal breast cancer, including both ER+ and ER negative BC subtypes. Overall, estrogen-dependent mechanisms have been implicated as the main driving force in obesity-related breast tumorigenesis. In the present review we discuss the epidemiologic and mechanistic aspects of association between obesity and breast tumors after menopause, mainly in the context of hormone dependency. Molecular and cellular events underlying this association present as potential avenues for both therapeutic intervention as well as the prevention of BC-promoting processes linked to excess adiposity, which is proving to be vital in an increasingly obese global population.

Androgen receptor-mediated pharmacogenomic expression quantitative trait loci: implications for breast cancer response to AR-targeting therapy.

BACKGROUND: Endocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80-90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies. METHODS: We performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog. RESULTS: We identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs. CONCLUSIONS: We identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.

A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer.

BACKGROUND: Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI). METHODS: In this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size. RESULTS: Our results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0-80); radiological-TS by USS 9 (0-31); by MRI: 12 (0-60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value. CONCLUSION: Our findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.

Effects of Letrozole Treatment and Vitamin C Supplementation on Morphology, Endoplasmic Reticulum Stress, Programmed Cell Death, and Oxidative Stress in the Small Intestine of Adult Male Rats.

Estrogens are hormones that play an important role in the digestive tract, including in men. Letrozole is an inhibitor of cytochrome P450 aromatase, an enzyme converting androgens to estrogens. The use of letrozole may cause oxidative stress and endoplasmic reticulum stress in the cells. Factors modulating cellular stress may include vitamin C. The purpose of this study was to examine whether letrozole and/or vitamin C supplementation can affect the morphology of the small intestine, the parameters of endoplasmic reticulum stress, programmed cell death markers, and oxidative damage. Three-month-old male rats were divided into four groups and treated with the following: (I) CTRL-water; (II) CTRL+C-L-ascorbic acid; (III) LET-letrozole; and (IV) LET+C-letrozole + L-ascorbic acid. The morphometrical measurements included epithelial thickness, crypt and lumen area, crypt perimeter, nuclei number in the crypt, and the cell size of crypts. The expression levels of PERK, caspase-3, and catalase were determined. Significant differences in the morphometrical measurements and immunoexpression were observed. This may indicate that chronic treatment with letrozole can affect morphology and induce ER stress, oxidative stress, and programmed cell death in the epithelial cells of the small intestine of adult male rats. Vitamin C supplementation exerts an effect on some parameters of the molecular processes.

Neuroestradiol and neuronal development: Not an exclusive male tale anymore.

The brain synthesizes a variety of neurosteroids, including neuroestradiol. Inhibition of neuroestradiol synthesis results in alterations in basic neurodevelopmental processes, such as neurogenesis, neuroblast migration, neuritogenesis and synaptogenesis. Although the neurodevelopmental actions of neuroestradiol are exerted in both sexes, some of them are sex-specific, such as the well characterized effects of neuroestradiol derived from the metabolism of testicular testosterone during critical periods of male brain development. In addition, recent findings have shown sex-specific actions of neuroestradiol on neuroblast migration, neuritic growth and synaptogenesis in females. Among other factors, the epigenetic regulation exerted by X linked genes, such as Kdm6a/Utx, may determine sex-specific actions of neuroestradiol in the female brain. This review evidences the impact of neuroestradiol on brain formation in both sexes and highlights the interaction of neural steriodogenesis, hormones and sex chromosomes in sex-specific brain development.

Validation of the RSClin risk calculator in the National Cancer Data Base.

BACKGROUND: Guidelines recommend the use of genomic assays such as OncotypeDx to aid in decisions regarding the use of chemotherapy for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. The RSClin prognostic tool integrates OncotypeDx and clinicopathologic features to predict distant recurrence and chemotherapy benefit, but further validation is needed before broad clinical adoption. METHODS: This study included patients from the National Cancer Data Base (NCDB) who were diagnosed with stage I-III HR+/HER2- breast cancer from 2010 to 2020 and received adjuvant endocrine therapy with or without chemotherapy. RSClin-predicted chemotherapy benefit was stratified into low (<3% reduction in distant recurrence), intermediate (3%-5%), and high (>5%). Cox models were used to model mortality adjusted for age, comorbidity index, insurance, and race/ethnicity. RESULTS: A total of 285,441 patients were identified for inclusion from the NCDB, with an average age of 60 years and a median follow-up of 58 months. Chemotherapy was associated with improved overall survival only for those predicted to have intermediate (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.60-0.79) and high benefit per RSClin (aHR, 0.66; 95% CI, 0.61-0.72). Consistent benefit was seen in the subset with a low OncotypeDx score (<26) and intermediate (aHR, 0.66; 95% CI, 0.53-0.82) or high (aHR, 0.71; 95% CI, 0.58-0.86) RSClin-predicted benefit. No survival benefit with chemotherapy was seen in patients with a high OncotypeDx score (≥26) and low benefit per RSClin (aHR, 1.70; 95% CI, 0.41-6.99). CONCLUSIONS: RSClin may identify high-risk patients who benefit from treatment intensification more accurately than OncotypeDx, and further prospective study is needed.

Endocrine therapy in advanced high-grade ovarian cancer: real-life data from a multicenter study and a review of the literature.

BACKGROUND: In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. PATIENTS AND METHODS: This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. RESULTS: Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (P = .021), an R0 surgical resection (P = .020), and the indication for hormone therapy being maintenance therapy (P = .002). CONCLUSION: This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.

Polypharmacy, over-the-counter medications, and aromatase inhibitor adherence in early-stage breast cancer.

PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation. METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence. RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation. CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.

Superior suppression of serum estrogens during neoadjuvant breast cancer treatment with letrozole compared to exemestane.

PURPOSE: The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking. METHODS: Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC-MS/MS method established in our laboratory. RESULTS: Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women. CONCLUSION: To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane.

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.

PURPOSE: We 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. METHODS: The 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. RESULTS: The 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. CONCLUSION: This 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).

Factors influencing the first and the fifth years adherence to adjuvant endocrine therapy in breast cancer patients in a low income country.

PURPOSE: Breast cancer is the leading cause of cancer death in Brazil and in many countries around the world. In order to minimize the risk of recurrence and death, adjuvant endocrine therapy (AET) is used in women whose tumors express hormone receptors; however, the therapy is associated with low rates of compliance. Therefore, we sought to evaluate the proportion of patients who are adherent/non-adherent to AET at the beginning of the therapy (1st year) and at its end (5th year). METHODS: Cross-sectional study assessing adherence through the Brief Medication Questionnaire. RESULTS: It was identified that eventual failures in maintaining the correct adherence to the treatment have risen from 23% of patients in the 1st year of treatment to 35% of patients in the 5th year (p = 0.005). In both groups, use of aromatase inhibitors, polypharmacy of at least 3 mediations and the previous diagnosis of diabetes mellitus (DM) or systemic arterial hypertension (SAH) have contributed to low adherence among patients. CONCLUSION: The proportion of patients who are not adherent to AET was high in both cohorts, and the rate of non-adherent patients rises over time. It is essential to incorporate screening methods for lack of compliance to AET, as well as measures to try to reduce non-persistence to the treatment, such as educating the patients on the benefits of the treatment, managing comorbidities through lifestyle changes and, therefore, reducing polypharmacy and, above all, detecting and treating very early the adverse effects of AET that might interfere with its correct use.

A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer.

BACKGROUND: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs). METHODS: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1ß, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up. RESULTS: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1ß and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1ß: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98). CONCLUSIONS: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

Comparative efficacy and safety of extended adjuvant endocrine therapy for hormone receptor-positive early breast cancer: a Bayesian network meta-analysis.

PURPOSE: Optimal extended adjuvant endocrine therapy (ET) duration and strategy for hormone receptor-positive (HR +) early breast cancer remain unclear. In this network meta-analysis (NMA), the efficacy and safety of all available extended adjuvant ETs were compared and ranked. METHODS: PubMed, Embase, and Cochrane Library and abstracts presented at ASCO, SABCS, and ESMO were searched on March 5, 2022. Fourteen randomized controlled trials (RCTs) comprising eight extended adjuvant ETs for HR + breast cancer and 38,070 patients were analyzed. Main outcomes were disease-free survival (DFS), overall survival (OS), grade ≥ 3 adverse events (AEs), and contralateral breast cancer (CBC). Direct and indirect comparisons were integrated via Bayesian NMA. Hierarchical cluster analysis was performed to jointly rank efficacy and safety outcomes. RESULTS: Compared with that of 5 year ET, extended 10 year aromatase inhibitor (AI) treatment provided the greatest DFS benefit (HR = 0.45, 95%CrI 0.23-0.83), whereas no strategy differed significantly in terms of the other main outcomes. Extended 10 year AI treatment was the preferred strategy for DFS improvement and CBC prevention (surface under the cumulative ranking curve: 93.51% and 91.29% probability, respectively). All strategies had comparable safeties (grade ≥ 3 AEs). Compared with that of 5 year ET, 10 year extended AI significantly increased arthralgia (OR = 1.65, 95%CrI 1.02-2.93) and osteoporosis (OR = 3.33, 95%CrI 1.19-9.68). CONCLUSION: Extended 10 year AI therapy may be optimal for HR + early breast cancer given its relatively high efficacy and safety.

Randomized placebo-controlled, double-blind clinical trial of nanoemulsion curcumin in women with aromatase inhibitor-induced arthropathy: an Alliance/NCORP pilot trial.

PURPOSE: Aromatase inhibitor (AI) therapy reduces risk of recurrence and death for postmenopausal women with breast cancer (BC); however, AI-induced arthralgia (AIIA) can lead to discontinuation of treatment. Curcumin, a bioactive polyphenolic substance, may help ameliorate inflammation-related conditions including osteoarthritis and pain. METHODS: We conducted a multisite randomized placebo-controlled, double-blind pilot trial (Alliance A22_Pilot9) to evaluate the effects of nanoemulsion curcumin (NEC, 200 mg/day) in postmenopausal women experiencing AIIA for ≥ 3 months. The primary objective was to determine the feasibility of using Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) to detect changes from 0 (T0) to 3 months (T3) of NEC treatment in AI-induced symptoms and well-being; secondary objectives included evaluation of changes in Disabilities of the Shoulder, Arm, and Hand (DASH), Brief Pain Inventory-short form (BPI-SF), grip strength, and biomarkers at T0 and T3. RESULTS: Forty-two patients were randomized to NEC or placebo; 34 women completed the 3-month study. Patient-reported outcome measures (PROMs: FACT-ES, DASH, BPI-SF) and biospecimens were collected at T0-T3 in > 80% of participants. Adherence was ≥ 90% for both arms. PROMs and grip strength did not differ significantly by treatment arm. Plasma curcumin was detected only in NEC arm participants. Serum estradiol and estrone levels were below detection or low on study agent. Gastrointestinal adverse effects were commonly reported in both arms. CONCLUSION: NEC versus placebo in a multisite randomized trial is feasible and well-tolerated. Additional studies with larger sample size are needed to further evaluate the efficacy and safety of NEC in treatment of AIIA. CLINICALTRIALS: gov Identifier: NCT03865992, first posted March 7, 2019.

Ovarian function recovery in breast cancer patients receiving adjuvant anastrozole treatment: updated results from the phase 3 DATA trial.

PURPOSE: Patients with chemotherapy-induced ovarian function failure (CIOFF) may experience ovarian function recovery (OFR). Earlier, we showed that OFR during treatment with anastrozole impacted the prognosis of hormone receptor-positive (HR+) breast cancer (BC) patients with CIOFF. Here, we present the long-term follow-up results. METHODS: Postmenopausal women with HR+ BC who were 45-57 years of age and received chemotherapy were identified from the phase 3 DATA study (NCT00301457) on the extended use of anastrozole. Eligible patients were categorised into two groups: patients with CIOFF and definitely postmenopausal patients. Patients with CIOFF were monitored for OFR. Disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS) were compared between patients with OFR and patients without OFR using multivariable Cox regression analyses, including OFR as a time-dependent covariate. BC-specific mortality (BCSM) was compared between groups using the Fine and Gray method. RESULTS: This study included 656 patients: 395 patients with CIOFF and 261 definitely postmenopausal patients. OFR occurred in 39 (12%) of 329 patients with CIOFF who were monitored for OFR. The median follow-up time was 13.3 years. Patients with OFR experienced a deterioration in DFS (hazard ratio (HR) = 1.54; 95% confidence interval (CI) 0.85-2.81), DRFS (HR = 1.51; 95% CI 0.73-3.11), OS (HR = 1.64; 95% CI 0.75-3.55), and BCSM (subdistribution HR = 1.98; 95% CI 0.84-4.63) when compared with patients without OFR. CONCLUSION: In patients with CIOFF, OFR during treatment with anastrozole was associated with a deterioration in BC outcomes. These findings underscore the importance of adequate ovarian function suppression in this subgroup of patients.

Factors associated with adherence to medications for lowering breast cancer risk between female Medicare beneficiaries in Alabama and nationwide.

PURPOSE: The U.S. Preventive Services Task Force recommends use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) for breast cancer (BC) prevention. We examined factors associated with adherence to SERMs/AI treatments among female Medicare beneficiaries in Alabama and those nationwide. METHODS: This retrospective new user cohort study analyzed the 2013-2016 Medicare administrative claims data files (100% Alabama and random 5% national samples). Female Medicare beneficiaries without invasive BC and osteoporosis, continuously enrolled in Medicare Parts A, B, and D for at least 18 months (with a 6-month washout and a 12-month follow-up period) in 2013-2016. Among beneficiaries who initiated (6-month washout) any of the SERMs/AIs (tamoxifen, raloxifene, anastrozole, and exemestane), we examined their 1-year treatment adherence using proportion of days covered (PDC) and operationalized as both continuous (0-1) and dichotomized (≥ 80% as adherent and < 80% as non-adherent) outcomes. Multivariable logistic models were used to identify factors associated with adherence (PDC ≥ 80%) among Alabama and national samples, respectively. RESULTS: A total of 885 women in Alabama and 1,213 women in national sample initiated these SERMs/AI treatments. Among those with ≥ 2 prescriptions (n = 479 in Alabama and n = 870 in national sample), Mean PDC was 0.74 [standard deviation (SD) = 0.30] among Alabamian women, similar to those in the national sample [0.71 (SD = 0.31), p = 0.09]. Use of mammography prior to treatment initiation was associated with higher likelihood of adherence to treatments in both samples. CONCLUSION: Our findings highlight the importance of access to preventive services such as mammography to better adherence to BC preventive treatments among female Medicare beneficiaries.

Estrogenic influences on agonistic behavior in teleost fishes.

Teleost fishes show an extraordinary diversity of sexual patterns, social structures, and sociosexual behaviors. Sex steroid hormones are key modulators of social behaviors in teleosts as in other vertebrates and act on sex steroid receptor-containing brain nuclei that form the evolutionarily conserved vertebrate social behavior network (SBN). Fishes also display important differences relative to tetrapod vertebrates that make them particularly well-suited to study the physiological mechanisms modulating social behavior. Specifically, fishes exhibit high levels of brain aromatization and have what has been proposed to be a lifelong, steroid hormone dependent plasticity in the neural substrates mediating sociosexual behavior. In this review, we examine how estrogenic signaling modulates sociosexual behaviors in teleosts with a particular focus on agonistic behavior. Estrogens have been shown to mediate agonistic behaviors in a broad range of fishes, from sexually monomorphic gonochoristic species to highly dimorphic sex changers with alternate reproductive phenotypes. These similarities across such diverse taxa contribute to a growing body of evidence that estrogens play a crucial role in the modulation of aggression in vertebrates. As analytical techniques and genomic tools rapidly advance, methods such as LC-MS/MS, snRNAseq, and CRISPR-based mutagenesis show great promise to further elucidate the mechanistic basis of estrogenic effects on social behavior in the diverse teleost lineage.