Inhibition Of Estrogen Synthesis Research Articles

Role function in postmenopausal women during aromatase inhibitor therapy for breast cancer.

Few studies have examined aromatase inhibitor therapy relating to role function in breast cancer survivors of working age. Our study sought to identify how pre-therapy sociodemographic and health/treatment-related characteristics, as well as patient-reported symptoms measured every six-months, influence role function during 18months of AI therapy for early-stage breast cancer. We performed a secondary analysis of longitudinal study data using linear mixed-effects modeling to examine role physical (RP) and role emotional (RE) functioning measured with the Medical Outcome Study Short Form 36 v2. The sample of postmenopausal women (N = 351) consisted of three cohorts: chemotherapy followed by anastrozole (CFAI), anastrozole only (AI only), and non-cancer controls. Our choice of variables and interpretation of findings was theoretically based on the Cancer Survivorship and Work Model. Stepwise backward deletion determined which predictors to include in the final model, accounting for treatment group. Both treatment groups were associated with greater limitations in RP functioning than controls. CFAI had twice the impact on RP compared to AI only. While the RP model displayed significant predictors across sociodemographic, health/treatment, and symptom characteristics, only symptoms were associated with greater limitations in RE functioning. Findings were significant at p < .05. Transitioning from acute to extended survivorship is a critical juncture in which multiple factors place breast cancer survivors at risk of diminished role function. Early interventions to address role function limitations during systemic treatment may lead to better work outcomes and improve the quality of long-term survivorship.

Retrospective Analysis of the Effect of Postmenopausal Women Medications on SARS-CoV-2 Infection Progression.

Since the beginning of the COVID-19 pandemic, it has been evident that women and young people were less susceptible to severe infections compared to males. In a previous study, we observed a reduced prevalence of SARS-CoV-2 infections in hormonal-driven breast cancer patients undergoing SERM (selective estrogen receptor modulator) therapy with respect to other treatments inhibiting estrogen synthesis. In addition to being used in anticancer therapy, SERMs are also prescribed for postmenopausal osteoporosis prevention and treatment. Therefore, in this study, a retrospective analysis of the clinical outcomes of SARS-CoV-2 infections in a population of women over 50 years who were treated for the management of menopausal symptoms was performed. SARS-CoV-2 infections, hospitalizations, and death rates were evaluated in women residing in the Italian north-eastern Veneto Region who were undergoing treatment with Estrogen Modulators (EMs); Estrogen or Progestin, and their combination (EPs); Bisphosphonates (BIs); or cholecalciferol (vitamin D3) ± calcium supplementation (CC). The final cohort study included 124,393 women, of whom 6412 were found to be SARS-CoV-2 infected (CoV2+ve). The results indicated that only women treated with vitamin D3 alone or in combination with calcium showed a significant reduction in their SARS-CoV-2 infection risk by 26% (OR 0.74; 95%CI 0.60-0.91). On the other hand, an increased risk of hospitalization (OR 2.69; 95%CI 1.77-4.07) was shown for the same treatments. The results highlighted in this work contribute to shedding some light on the widely debated role of vitamin D in the prevention of SARS-CoV-2 infections and the disease's treatment.

Artificial Intelligence on The Couch. Staying Human Post-AI.

This paper examines the human relationship to technology, and AI in particular, including the proposition that algorithms are the new unconscious. Key is the question of how much human abilitywill be duplicated and transcended by generalmachine intelligence. More and more people are seeking connection via social media and interaction with artificial beings. The paper examines what it means to be human and which of these traits are already or will be replicated by AI. Therapy bots already exist. It is easier to envision AI therapy guided by CBT manuals than psychoanalytic techniques. Yet, a demonstration of how AI can already perform dream analysis reaching beyond a dream's manifest content is presented. The reader is left to consider whether these findings demand a new role for psychoanalysis in supporting, sustaining, and reframing our humanity as we create technology that transcends our abilities.

Risk of ocular adverse events with aromatase inhibitors

ObjectifLes inhibiteurs de l'aromatase (IA) forment une classe de médicaments utilisés dans le traitement adjuvant du cancer du sein. Or, des cas cliniques récents semblent indiquer que les IA pourraient être associés à différents effets indésirables (EI) oculaires. Notre étude se penche sur le risque d'EI oculaires chez les patients qui prennent des IA. MéthodeOn s'est servi de la base de données sur les effets indésirables (Adverse Events Reporting System) de la Food and Drug Administration (FDA) américaine pour les années 2004 à 2022 afin de réaliser une analyse de disproportionnalité. On a extrait tous les cas d'effets secondaires oculaires (traction vitréomaculaire, œdème maculaire, dépôts rétiniens, occlusion de l'artère rétinienne, trou maculaire, hémorragie rétinienne, uvéite, déchirure de la rétine, décollement de rétine, sécheresse oculaire, blépharite et neuropathie optique) en lien avec l'administration des 3 IA (anastrozole, létrozole et exémestane). À titre de groupe témoin, on a procédé à la même recherche sur le trastuzumab. Ont été calculés les rapports de cotes (ROR, pour reported odds ratios) et les intervalles de confiance (IC) à 95 % correspondants. RésultatsNous avons découvert 322 EI oculaires d'intérêt en lien avec l'administration des 3 IA et 55 EI en lien avec l'administration du trastuzumab. L'anastrozole a eu le plus grand nombre d'EI (n = 163); on a enregistré une forte association entre ce médicament et la traction vitréomaculaire (ROR = 665; IC à 95 % : 352–1255), l’œdème maculaire (ROR = 37; IC à 95 % : 25–54), les dépôts rétiniens (ROR = 11; IC à 95 % : 2–77) et l'uvéite (ROR = 6; IC à 95 % : 4–9). On a observé une forte association entre le létrozole et les dépôts rétiniens (ROR = 8; IC à 95 % : 1–57) et l'occlusion des artères rétiniennes (ROR = 6; IC à 95 % : 3–11). Enfin, on a noté une forte association entre l'exémestane et les trous maculaires (ROR = 10; IC à 95 % : 3–30). ConclusionL'analyse de disproportionnalité a mis au jour une hausse du risque d'EI oculaires en lien avec chacun des IA. Compte tenu des résultats de notre étude, il est important que les médecins, surtout les oncologues et les ophtalmologistes, fassent preuve de vigilance chez les patients qui reçoivent des IA pour pouvoir intervenir sans délai afin d’éviter la survenue d'autres affections oculaires.

279P Early changes in bone turnover biomarkers during AI therapy are related to loss bone mineral density, data of the B-ABLE cohort

279P Early changes in bone turnover biomarkers during AI therapy are related to loss bone mineral density, data of the B-ABLE cohort

FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer

BackgroundObesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression.MethodsWe explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity.ResultsFGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells.ConclusionsCollectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.

Promoting physical activity through supervised vs motivational behavior change interventions in breast cancer survivors on aromatase inhibitors (PAC-WOMAN): protocol for a 3-arm pragmatic randomized controlled trial

BackgroundAromatase inhibitors (AI) are frequently used to treat hormone-receptor-positive breast cancer, but they have multiple adverse effects (e.g., osteoporosis, arthralgia), resulting in premature therapy discontinuation/switch. Physical activity (PA) can attenuate these negative effects and improve quality of life (QoL). However, most cancer survivors fail to perform/sustain adequate PA levels, especially in the long-term. Theory-based interventions, using evidence-based behavior change techniques, aimed at promoting long-term behavior change in breast cancer survivors are effective, but remain scarce and fail to promote self-regulatory skills and better-quality motivations associated with sustained PA adoption. This paper describes the design of the PAC-WOMAN trial, which will test the long-term effectiveness and cost-effectiveness of two state of the art, group-based interventions encouraging sustained changes in PA, sedentary behavior, and QoL. Additional aims include examining the impact of both interventions on secondary outcomes (e.g., body composition, physical function), and key moderators/mediators of short and long-term changes in primary outcomes.MethodsA 3-arm pragmatic randomized controlled trial, involving a 4-month intervention and a 12-month follow-up, will be implemented, in a real exercise setting, to compare: 1) brief PA counseling/motivational intervention; 2) structured exercise program vs. waiting-list control group. Study recruitment goal is 122 hormone-receptor-positive breast cancer survivors (stage I-III), on AI therapy (post-primary treatment completion) ≥ 1 month, ECOG 0–1. Outcome measures will be obtained at baseline, 4 months (i.e., post-intervention), 10 and 16 months. Process evaluation, analyzing implementation determinants, will also be conducted.DiscussionPAC-WOMAN is expected to have a relevant impact on participants PA and QoL and provide insights for the improvement of interventions designed to promote sustained adherence to active lifestyle behaviors, facilitating its translation to community settings.Trial registrationApril 20, 2023 – NCT05860621.April 21, 2023 – https://doi.org/10.17605/OSF.IO/ZAQ9NApril 27, 2023 – UMIN000050945.

Abstract WS1-2: How to measure and improve drug adherence in clinical trials

Abstract The past decade has seen a dramatic increase in the number of Food and Drug Administration approval of oral anti-cancer drugs (OACDs). In 2018 alone, OACDs comprised ten of the sixteen newly approved oncology therapeutics in the United States. Despite the clinical benefits and convenience of OACDs, these new oral options present potential challenges, including polypharmacy, and can result in increased toxicities, drug–drug interactions (DDIs), inappropriate consumption of medications, and medication non-adherence. Adverse drug events have the potential to affect quality of life, healthcare utilization, treatment response, and survival. For the treatment of breast cancer, Endocrine therapies have remained a critical component of care for early stage and advance disease. Despite the proven efficacy adherence to therapy is suboptimal. Issues related to non-adherence are increasingly important, as analyses from prospective randomized trials show compliance to endocrine therapy is associated with improved disease-free survival. The reasons for non-adherence to hormonal therapy are multifactorial. Barriers to compliance include patient, physician, medication and system related variables and poor compliance is usually associated with a combination of these factors. Characteristics associated with non-adherence include very high and low age, minority race, being single, increased number of comorbidities, lack of knowledge about efficacy of AI therapy, history of non-adherence to other chronic medications, limited insurance status, and higher out of pocket costs. Side effects from hormonal therapy is the most common reason for early discontinuation. An understanding of factors that contribute to non-adherence and interventions that have been tested to improve adherence will be discussed. Medication compliance has become a more salient issue in cancer care with the increased availability of oral antineoplastic therapies for breast cancer. The treatment of BC now routinely encompasses targeted therapies such as oral poly(ADP-ribose) polymerase (PARP) inhibitors and cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors, PI3 Kinase(Pi3K) Inhibitors, in addition to traditional ET. Furthermore, as advances in BC treatment have improved long-term prognosis, the management of other chronic conditions has become an essential component of BC survivorship care. It remains unclear how this increased oral medication burden on BC survivors affects compliance with both ET and other chronic medications. Issues related to adherence measurement will be discussed. Citation Format: Dawn Hershman. How to measure and improve drug adherence in clinical trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS1-2.

Testolactone: The Rise and Fall of a Drug

Testolactone is structurally related to testosterone and belongs to the first generation of aromatase inhibitors. It is a non-selective irreversible aromatase enzyme inhibitor that was one of the first steroids used in the clinical treatment of breast cancer. The use of testolactone in the treatment of breast cancer started in 1970, although its ability to inhibit aromatase was not discovered until 1975. Its use was primarily based on the inhibition of estrogen synthesis, which was applied in the treatment of estrogen-dependent breast cancers, in the treatment of disorders of sex steroid excess, familial male-limited precocious puberty, or in the treatment of patients with McCune–Albright syndrome, etc. The weak inhibitory activity of testolactone, and the moderate clinical response, prevented its widespread use, which ultimately resulted in withdrawal from the drug market in 2008. This review paper is dedicated to testolactone, its rise in the second half of the 20th century, and its fall in the first decade of the 21st century. Regardless of withdrawal from the market, for many years testolactone was a drug that improved the quality of life of patients facing one of the most serious diseases today, and for this reason, this paper describes medicinal application, synthesis, and modifications of testolactone.

IPSCs-derived mesenchymal stromal cells mitigate anxiety and neuroinflammation in aging female mice.

Perimenopause is a natural transition to menopause, when hormone disturbance can result in both short-term mental disorders, such as anxiety, and long-term neuroinflammation due to blood-brain barrier (BBB) impairment, which may lead to more serious neurological disorders later on, such as dementia. Effective treatments may prevent both short-term and long-term neurological sequela, which formed the aim of this study. In aged female C57BL/6 mice (16-18 months of age), mesenchymal stromal cells (MSCs) differentiated from human-induced pluripotent stem cells (iPSCs), were administered via tail vein injection. Mice showed increased blood estrogen levels, alleviated anxiety and neuroinflammation, and improved BBB integrity. Interestingly, transplanted MSCs were located close to ovarian sympathetic nerves and decreased ovarian norepinephrine levels, which in turn increased ovarian estrogen secretion. Moreover, the administration of anastrozole, an inhibitor of estrogen synthesis, diminished the therapeutic effects of MSCs in vivo, suggesting the effect to be estrogen-dependent. In vitro study confirmed the impact of MSCs on sympathetic nerves via mitochondria exchange. In conclusion, iPSC-derived MSCs may provide a novel option to manage perimenopause-related hormonal dysregulation and neurological disorders during the female aging process.

Amh/Amhr2 Signaling Causes Masculinization by Inhibiting Estrogen Synthesis during Gonadal Sex Differentiation in Japanese Flounder (Paralichthys olivaceus).

The anti-Müllerian hormone (Amh) is a protein belonging to the TGF-β superfamily, the function of which has been considered important for male sex differentiation in vertebrates. The Japanese flounder (Paralichthys olivaceus) is a teleost fish that has an XX/XY sex determination system and temperature-dependent sex determination. In this species, amh expression is up-regulated in genetic males and in temperature-induced masculinization during the sex differentiation period. However, to the best of our knowledge, no reports on the Amh receptor (Amhr2) in flounder have been published, and the details of Amh signaling remain unclear. In this study, we produced amhr2-deficient mutants using the CRISPR/Cas9 system and analyzed the gonadal phenotypes and sex-related genes. The results revealed that the gonads of genetically male amhr2 mutants featured typical ovaries, and the sex differentiation-related genes showed a female expression pattern. Thus, the loss of Amhr2 function causes male-to-female sex reversal in Japanese flounder. Moreover, the treatment of genetically male amhr2 mutants with an aromatase inhibitor fadrozole, which inhibits estrogen synthesis, resulted in testicular formation. These results strongly suggest that Amh/Amhr2 signaling causes masculinization by inhibiting estrogen synthesis during gonadal sex differentiation in the flounder.

ESR1-мутації як предиктор прогресії та метастазування гормонозалежного раку молочної залози

The relevance of the work is due to the need for additional research to better understand the prevalence of ESR1 mutations at different stages of recurrent disease and their prognostic implications. The purpose of the study was to determine the incidence of ESR1 mutations in ER-positive breast cancer, its prognostic value in the choice of treatment. Materials and methods. A systematic review of quality studies, which were taken from PubMed and Thomas Reuters Web of Science databases, published between 2007 and 2019 was performed. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrence, metastasis, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English on the development of ESR1 mutations and their outcomes on disease progression were included. Studies were selected using predefined data fields, taking into account the quality of the study. This prospective clinical study is conducted by means of molecular genetic analysis, namely, gene polymorphism analysis by polymerase chain reaction. This study is carried out on the basis of the Kyiv City Clinical Oncology Center and the Department of Oncology of the Bogomolets National Medical University. A retrospective cohort of hormone receptor positive breast cancer patients experiencing either local or metastatic recurrence was collected from available archival specimens. All clinical data were obtained from the patients' clinical records by an expert breast oncologist. This included age, TNM stage, grade, immunohistochemistry scores for estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and treatment lines. Results and discussion. Estrogen receptor and progesterone receptor positivity was determined based on local pathology practice (&gt; 1% positively stained cells). The article demonstrated that ESR1 mutations often occur during AI therapy in the setting of metastasis and may play a role in metastasis progression. Advances in DNA sequencing technology have led to more sensitive detection of ESR1 mutations in clinical samples, and there are now several studies using sequencing and ddPCR techniques to track ESR1 and other mutations during treatment and progression. Targeted DNA sequencing and ddPCR technologies have shown that ESR1 mutations may pre-exist in approximately 5% of primary tumors and are significantly enriched by 30-40% in the setting of metastasis. The ctDNA analysis provides a simple, non-invasive and relatively inexpensive method for monitoring mutations that may arise during treatment, which can ultimately be used to guide treatment decisions. Conclusion. Importantly, ESR1 mutation monitoring alone is not clinically predictive of treatment; however, monitoring the acquisition of stem cell or other mutations may predict response and/or progression of treated cancers. Currently, patients with tumors expressing ESR1 mutations are best treated with the combination of fulvestrant and palbociclib, as this combination has significantly improved PFS in patients with most identified ESR1 mutations. Ongoing clinical trials using fulvestrant with specific PI3K-alpha inhibitors are showing promising clinical results, but analysis of whether patients with specific ESR1 mutations will benefit from this treatment has not yet been published

Increased Clinical Pain Locations and Pain Sensitivity in Women After Breast Cancer Surgery: Influence of Aromatase Inhibitor Therapy.

Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome). However, the link between AIs and number of clinical pain locations and pain sensitivity are less well understood. The aim of this study was to compare longitudinal changes in clinical pain and quantitative pain sensitivity between women who did or did not receive AI therapy. Women with early-stage breast cancer were prospectively enrolled and assessed for clinical pain in surgical and nonsurgical body areas using the Brief Pain Inventory and Breast Cancer Pain Questionnaire, and for pain sensitivity using quantitative sensory testing preoperatively and at 1 year postoperatively. Pain outcomes between participants who did and did not begin adjuvant AI therapy were compared using Wilcoxon Signed-Ranks and generalized estimating equation linear regression analyses. Clinical pain and pain sensitivity were comparable between AI (n=49) and no-AI (n=106) groups preoperatively. After adjusting for body mass index, AI therapy was associated with a greater increase in the number of painful nonsurgical body sites (significant time by treatment interaction, P =0.024). Pain location was most frequent in knees (28%), lower back (26%), and ankles/feet (17%). Quantitative sensory testing revealed a significant decrease in pain sensitivity (increased pressure pain threshold) in the no-AI group over time, but not in the AI group. AI therapy was associated with increased diffuse joint-related pain and greater post-treatment pain sensitivity, potentially implicating central sensitization as a contributing pain mechanism of aromatase inhibitor-associated musculoskeletal syndrome worthy of future investigation.

Carbidopa suppresses estrogen receptor-positive breast cancer via AhR-mediated proteasomal degradation of ERα.

Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.

A novel AI therapy for depression counseling using face emotion techniques

Depression or stress is faced by most of the population throughout the world for multiple reasons and at different stages of life. Due to present busy life cycle, humans get into stress in their daily life, which leads to depression on long term. Stress is faced in education activity, competitive / challenging tasks, work pressure, family consequences, different types of human relation management, health disorders, old age etc. In this paper, a novel Artificial Intelligence therapy for depression analysis is proposed. This research is helpful for Psychologist to conduct counselling for their patients. Machine learning based Face Emotion techniques are used to detect depression level in any patient. This model can be tested for any age / category of patient, who faces depression due to any kind of problem or different sequences of life. To train machine learning algorithm, fer2013 open-source dataset is used. The algorithm was well trained and experiment were conducted on different age people. The results of this proposed algorithm were able to analyze depression more effectively.

Aromatase Inhibitors: Development and Current Perspectives

Abstract: Aim: Breast cancer is one of the most common cancers among women, consistently elevated estrogen level in the blood associated with persistently in breast cancer found in many studies. The mechanisms of carcinogenesis whereby cancer is associated involved in the conversion of androgen to estrogen in the presence of enzyme aromatase. Materials and Methods: Aromatase is a (CYP19), a cytochrome P450, which is the enzyme that synthesizes estrogen. Aromatase which is expressed in higher concentration in breast play a pivotal role in the origin and progression of breast cancer. In situ inhibition of aromatase enzyme accomplished by the prevention of aromatase expression in breast cancer. Results: The success of aromatase inhibition could result in the suppression and progression of breast cancer. One of the ways to reduce the incidence of breast cancer by inhibiting estrogen biosynthesis in breast tissue. Aromatase inhibitor therapy is considered for second-line treatment in patients who fail anti-estrogen therapy. Conclusion: Several potent and selective aromatase inhibitors have been developed and used to treat breast cancer. Some of them have passed clinical trial phase II. Development in the field has encouraged us to review work on the Aromatase inhibitor. Key words: Non-Steroidal aromatase inhibitor, Aromatase, Cancer, Aromatase Inhibitors.

Molecular modeling and ADMET predictions of flavonoids as prospective aromatase inhibitors

With the advent of a myriad of treatment possibilities for breast cancer, enzyme inhibition turns out to be the prevailing strategy for inhibiting estrogen biosynthesis. Aromatization of ring A of androstenedione, testosterone and 16a-hydroxytestosterone results in increased estrogen level, which embraces the risk for breast cancer. In this present research, we have targeted human placental aromatase complexed with HDDG046 (PDB ID: 4GL7) for its inhibition by several inhibitors of flavonoid derivatives and further screening those molecules for ADMET properties for assessing its credibility for acceptance in successive steps of drug discovery. Novel flavonoid derivative molecules have been designed using Maestro 10.4, based on the literature review. Further, their molecular modeling studies have been performed against the imported target PDB ID: 4GL7 using the GLIDE platform and have been subjected to ADMET assessment using the QikProp and pkCSM program. From all the series exposed to molecular modeling; 2K, 4K, 6K, 8W and 10K molecules have been subjected to ADMET study based on their interaction profile. Successively screening of these molecules led to selection of 8W molecule for further validation by pkCSM. The results obtained have been compared with the reported molecule HDDG046 which presents substantially positive outcomes for 8W in terms of CaCo2 permeability, water solubility, P- glycoprotein; hERG I, II and CYP interactions, hepatotoxicity, LD50 value and so forth. Juxtaposing the results of all the designed molecules under study, we have established that these prospective molecules especially 8W of flavonoid derivatives have the potency to inhibit the target under study, which can be useful in the treatment of breast cancer. This has been estimated based on the in silico approaches performed using Molecular Modeling which utilizes the integral function of Molecular Mechanics and Quantum Mechanics. In addition, the ADMET predictions validate their integrity for being the lead molecules in drug discovery stages in the near future.

Feasibility Trial to Evaluate Tendon Stiffness Obtained from Shear Wave Elastography Imaging as a Biomarker of Aromatase Inhibitor-Induced Arthralgias

Aromatase inhibitor-induced arthralgia (AIA) comprises significant, activity-limiting musculoskeletal symptoms, including joint pain, myalgia, and joint stiffness. We conducted a prospective feasibility study in postmenopausal women diagnosed with early-stage (0–3) hormone receptor positive (HR+) breast cancer who were candidates for treatment with adjuvant AI therapy (n = 16). Tendons of the hands and wrists and the median nerve were imaged using gray-scale and power Doppler ultrasound (US) and US SWE. Arthralgia symptoms were evaluated using the Breast Cancer Prevention Trial (BCPT) Symptom Checklist musculoskeletal subscale (MS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness subscales. At baseline, there were significant differences in the SW velocities of tendons between dominant and nondominant hands. Increased velocity in 2 of 6 tendons and the median nerve was associated with greater pain at baseline, whereas slower velocity of the extensor digitorum tendon (suggesting decreased stiffness) was associated with a higher WOMAC stiffness score. Increased SW velocity (suggestive of increased stiffness) at baseline in the abductor pollicis longus tendon was associated with a worsening of all three pain and stiffness measures by 6 months. Future studies should evaluate SWE scores related to AIA outcomes in a larger sample size.

Abstract P2-11-05: Generating real-world external comparators for randomized clinical trials (RCTs) in metastatic breast cancer (mBC) using electronic health records (EHRs)

Abstract Objectives: Real-world data (RWD) from the routine care of patients with cancer captured through EHRs is a valuable resource for research. Understanding the relationship between characteristics and outcomes of patients treated in the real world and those treated in clinical trials is essential to produce evaluable trial-like populations using RWD in oncology for research and regulatory purposes. Methods: This study used: a) RWD from the Flatiron Health EHR-derived, de-identified, longitudinal database (comprising patient-level structured and unstructured data, curated via technology-enabled abstraction selected from approximately 280 US cancer clinics [~800 sites of care]) and b) patient-level data from three completed RCTs (PALOMA-2, MONALEESA-2, and MONARCH-3) including patients with previously untreated hormone receptor positive (HR+), HER2/neu negative (HER2-) mBC, then separately pooled across the trials into two treatment groups, patients who received aromatase inhibitor monotherapy (AI) or a CDK4/6 inhibitor + AI. Key eligibility criteria were similar across the RCTs and were used to select a real world external cohort (rwEC) initiating AI monotherapy on or prior to 11 Nov 2015 (end of MONARCH-3 enrollment period). Patients from the rwEC were matched separately to the control arm and experimental arm patients from the pooled RCT using propensity score method (PSM). The propensity score was estimated by a logistic regression using baseline covariates of age, race, site of disease (visceral, non-visceral), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0, 1), and metastatic disease (recurrent, new). The matching ratio was 1:1 without replacement with calipers. Covariate balance was measured by the absolute standardized mean difference (ASMD). Due to the high percentage of missing ECOG PS data, matching was repeated 100 times with imputed ECOG PS. The impact of including additional key covariates for propensity matching such as number of disease sites, bone-only disease, and prior endocrine therapy was assessed. Results: There were 1326 patients with HR+, HER2- mBC selected from the EHR-derived database who received first-line AI therapy and 1827 patients randomized in the RCTs (1106 and 721 patients for experimental and control arms, respectively). With 100 matching iterations, 563 rwEC patients on average (range, 547-572) were matched to the RCTs control arm, and 753 rwEC patients on average (range: 741-761) were matched to the RCTs experimental arm. Prior to matching, the ASMD varied widely across all prespecified baseline covariates (4.3 for the rwEC vs. RCTs control arm, 2.6 for the rwEC vs. RCTs experimental arm). After matching was performed, across all baseline covariates used in the PSM, the ASMD was reduced to be under 0.12 for the rwEC vs. RCTs control arm, and under 0.2 for the rwEC vs. RCTs experimental arm in more than 90% of the matching iterations. Analyses looking at the additional baseline covariates to the propensity matching resulted in similar ASMDs. Conclusions: EHR-derived RWD can be used to generate a cohort of patients with similar baseline characteristics to those treated on RCT. The next step in our trial emulation framework is to analyze the comparability of outcomes between these two matched cohorts. Citation Format: Laleh Amiri-Kordestani, Xin Gao, Shrujal Baxi, Erik Bloomquist, Jonathan Bryan, Lynn Howie, Catherine Keane, Paul G. Kluetz, Christy Osgood, Prashni Paliwal, Donna R. Rivera, James Roose, Julie Schneider, Harpreet Singh, Shenghui Tang, Lijun Zhang, Julia A. Beaver. Generating real-world external comparators for randomized clinical trials (RCTs) in metastatic breast cancer (mBC) using electronic health records (EHRs) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-05.

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.