Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.

Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.

Use of aromatase inhibitors in menopausal deep endometriosis: a case report and literature review.

We report and review the clinical effectiveness of aromatase inhibitors in a patient with refractory, recurrent and infiltrating endometriosis. We demonstrate excellent clinical, radiological and endoscopic responses after failure of multiple other modalities. Our case and the literature show that single-agent letrozole is capable to treat deep infiltrative endometriosis involving the rectum and the urinary tract. The use of aromatase inhibitor treatment of endometriosis in postmenopausal women makes sense, is safe and is well tolerated. Difficult cases of deep infiltrative endometriosis might require use of combined surgical and medical treatment modalities. Multidisciplinary involvement of the gynecologist, bowel surgeon, urologist and invasive radiologist might be needed. Aromatase inhibitors should be considered to be an integral part of the armamentarium in the management of women with endometriosis, especially in refractory cases that have failed conventional therapeutic modalities.

Targets in anticancer research--A review.

Cancer is a complex disease characterized by a loss in the normal cell regulatory mechanisms that govern cell survival, proliferation, and differentiation. Current chemotherapeutics, as anticancer agents, are developing resistance to single drug and also to treatment therapies involving multiple drugs. Cross resistance associated with the specificity and selectivity of existing drugs has restricted the application of chemotherapy. Alternatively, these limitations have given better insight in understanding the underlying molecular mechanisms responsible for the development of various stages in cancer. In the light of this, continuous efforts are being made in order to identify and validate newer anticancer targets. This review presents some of the important targets that have been already reported, such as aromatase, farnesyl transferase, histone deacetylase, tyrosine kinase and cyclin-dependent kinase. A few molecules designed against these targets have successfully reached clinical trials. However, only limited marketed drugs are available from these classes. Besides, the review also highlights some of the other important targets and strategies that have also drawn considerable attention in the area of anticancer drug development such as, cancer stem cells and monoclonal antibodies. Further, the integration of the tools in molecular biology with the results from preclinical and clinical trials would strengthen the effectiveness of treatment regimens in cancer patients. There lies a much scope for designing promising lead compounds and treatment therapies against these established targets.

A Systematic Review of Systematic Reviews on the Use of Aromatase Inhibitors for the Treatment of Endometriosis: The Evidence to Date.

Endometriosis is a chronic gynecologic condition that affects around 6-10% of reproductive age women. This clinical entity is characterized with pelvic pain, dysmenorrhea, dyspareunia, and infertility which are the most often presenting symptoms. Aromatase P450 is the key enzyme for ovarian estrogen biosynthesis and there is evidence that endometriotic lesions express aromatase and are able to synthesize their own estrogens. Aromatase inhibitors (AIs) are potent drugs that suppress the estrogen synthesis via suppression of aromatase. We performed a systematic review of systematic reviews and narrative reviews on the use of aromatase inhibitors in the medical management of endometriosis. We searched: PubMed (1950-2022), Google Scholar (2004-2022), Cochrane Library (2010-2022) and Researchgate (2010-2022). The search included the following medical subject headings (MeSH) or keywords: "Aromatase Inhibitors" AND "Endometriosis" AND "Systematic reviews" OR "Systematic review" AND "Reviews" OR "Reviews" AND "Endometriosis". The electronic database search yielded initially 12,106 studies from the different databases. Further assessment of the studies resulted in exclusion of (n = 12,015) studies due to duplicates and irrelevance; Finally, 24 studies were selected for inclusion, 5 were Systematic reviews and 19 were Narrative reviews. The 5 systematic reviews were assessed by AMSTAR-2 criteria and were found to have low quality. Narrative reviews were assessed with SANRA criteria and were found to have high-quality aromatase inhibitors are potent drugs that can manage the endometriosis-related symptoms in cases where initial medical management has failed to show positive results. However, their use is limited by the adverse effects that are linked with menopausal symptoms. aromatase inhibitors can be administered as an alternative treatment in patients. Future studies with randomized design are required to reach safer conclusions and further investigation. These studies should define the therapeutic dose, new add-back therapy modalities. Future directions should examine the most-appropriate way of administration and the duration of therapy.

BMX controls 3ßHSD1 and sex steroid biosynthesis in cancer.

Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3ß-hydroxysteroid dehydrogenase-1 (3ßHSD1) serves as the rate-limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3ßHSD1 in driving CRPC. In postmenopausal women, 3ßHSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3ßHSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3ßHSD1 cellular activity and generation of Δ4, 3-keto-substrates of 5α-reductase and aromatase, including in patient tissues. BMX directly interacts with 3ßHSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3ßHSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.

Identification of Non-steroidal Aromatase Inhibitors via In silico and In vitro Studies

INTRODUCTION: Breast cancer is the most common cancer affecting women worldwide, including Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer, which is developed due to the over-production of estrogen (the main hormone in breast cancer). METHOD: The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as a target for the treatment of breast cancer. During the current study, biochemical, computational, and STD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3- butene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 µM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 = 0.0147 ± 1.45 µM), anastrozole (IC50 = 0.0094 ± 0.91 µM), and exemestane (IC50 = 0.2 ± 0.032 µM). Kinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively. RESULT: Docking studies on all active compounds indicated their binding adjacent to the heme group and interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme. CONCLUSION: STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be non-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified new aromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research.

The Role of Aromatase Enzyme in Hormone Related Diseases and Plant- Based Aromatase Inhibitors as Therapeutic Regimens.

Medicinal plants have a long history of use as food and remedy in traditional and modern societies. They have been used as herbal drugs and sources of novel bioactive compounds. They provide a wide array of chemical compounds, many of which can not be synthesized via current synthesis methods. Natural products may provide aromatase inhibitory activity through various pathways and may act clinically effective for treating pathologies associated with excessive aromatase secretion, including breast, ovarian, and endometrial cancers, endometriosis, uterine fibroid, benign prostatic hyperplasia (BPH), prostate cancer, infertility, and gynecomastia. Recent studies have shown that natural products with aromatase inhibitory activity can also be good options against secondary recurrence of breast cancer by exhibiting chemopreventive effects. Therefore, screening for new plant-based aromatase inhibitors may provide novel leads for drug discovery and development, particularly with increased clinical efficacy and decreased side effects.

Placental aromatase expression decreased in severe neonatal opioid withdrawal syndrome.

Background: Severe neonatal opioid withdrawal syndrome (NOWS) cannot be predicted. Placental aromatase metabolizes both methadone and buprenorphine and may contribute to the severity of NOWS.Objectives: To determine whether placental aromatase mRNA expression differs in methadone- or buprenorphine-exposed placentas and is associated with NOWS severity.Study design: Prospective multicenter observational cohort study from July 2016 to December 2017. Inclusion: pregnant, ≥18 years old, singleton fetus, nonanomalous, ≥34 weeks at delivery, documented methadone or buprenorphine use. Exclusion: declined sample collection. Severe NOWS is defined as three consecutive Finnegan scores ≥8 or sum of three consecutive scores ≥24 within 72 hours of birth. Finnegan scoring was correlated with placental mRNA expression and compared to umbilical cord drug and metabolite levels. Data were analyzed using descriptive, parametric, and nonparametric statistics and regression analysis. p-Value <.05 was considered significant.Results: Thirty-eight out of 45 (84%) patients were included. Methadone and buprenorphine were used by 29/38 (76%) and 9/38 (24%) of patients, respectively. 19/38 (50%) infants had severe NOWS. Placental aromatase/actin mRNA expression was significantly lower in the placentas of infants with severe NOWS (p = .04). Mean umbilical cord 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)/methadone ratios were significantly higher in infants with severe NOWS (p = .03). Placental aromatase mRNA expression was weakly to moderately correlated with umbilical cord methadone, buprenorphine, and their metabolite concentrations (r = 0.4-0.8).Conclusion: Placental aromatase mRNA expression was lower and umbilical cord EDDP/methadone ratios were higher in infants with severe NOWS. Additional investigation of placental aromatase in methadone- and buprenorphine-exposed pregnancies is needed.

[Current status of breast cancer chemoprevention]. / Quimioprevenção do câncer de mama.

Chemoprevention is defined as the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic progression of invasive cancer. Drugs that act as chemoprevention agents for breast cancer are divided into two major groups: drugs that prevent Estrogen Receptor (ER)-positive breast cancers [selective estrogen receptor modulators (SERM), aromatase inhibitors GnKH agonists and phytoestrogens] and drugs that prevent ER-negative breast cancers [cyclooxygenase-2 (COX-2) inhibitors, retinoids, statins, receptor tyrosine, kinase inhibitors, monoclonal antibody against HER-2 and telomerase inhibitors]. Results from the NSABP Study of Tamoxifen and Raloxifene (STAR), which compared the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk for breast cancer population, showed that Raloxifene is as effective as Tamoxifen in reducing the risk of non-invasive breast cancer (p=.83). It has a statistically significant lower risk of thromboembolic events and cataracts, however a non- statistically significant higher risk of noninvasive breast cancer. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole and exemestane, are being included in trials to evaluate their efficacy in breast cancer prevention in both case-control and cohort studies As such randomized studies to confirm this efficacy are needed. Positive results of several recent clinical trials for preventing breast cancer in high-risk populations suggest that chemoprevention is a rational and attractive strategy.

Formestane. A review of its pharmacological properties and clinical efficacy in the treatment of postmenopausal breast cancer.

Formestane (4-hydroxyandrostenedione) is an aromatase inhibitor which significantly reduces plasma levels of estrogen and has shown antitumour activity in postmenopausal women with breast cancer. Objective response rates in heavily pretreated patients with advanced breast cancer generally range between 20 and 30% during treatment with intramuscular formestone 250 or 500mg once every 2 weeks, and a further 20 to 30% of patients experience disease stabilisation. The median duration of response is between 8 and 14 months. Highest response rates are observed in soft tissue metastases, in patients with estrogen-responsive tumours and in those showing a response to previous endocrine therapy. Furthermore, there is some evidence to suggest that higher response rates are achieved with formestane 500 versus 250mg once every 2 weeks. In comparative studies, the clinical efficacy of intramuscular formestane 250mg did not differ significantly from that of oral megestrol when administered as second-line endocrine therapy to patients with advanced disease in whom previous tamoxifen therapy had failed. In addition, formestane produced a response rate, duration of response and overall survival rate that was not significantly different from that of oral tamoxifen when administered as first-line endocrine therapy to patients with advanced disease, but tamoxifen was superior in some measures. Further investigation of these 2 agents, including the higher dosage of formestane (500mg), is necessary to confirm their relative efficacies. Formestane is well tolerated by the majority of patients; adverse events rarely necessitate cessation of therapy. The most common adverse events are local reactions at the injection site and systemic events usually related to the effect of the drug on the hormonal milieu. The systemic tolerability of formestane is similar to that of tamoxifen but better than that of megestrol. Thus, formestane is effective and well tolerated as first-line endocrine therapy for advanced disease. However, at present, it is unlikely to challenge tamoxifen in this indication, based on recent findings from a large comparative study and the fact that formestane requires intramuscular administration. Nonetheless, formestane, which appears to have a better tolerability profile than other currently available second-line agents (including megestrol and the aromatase inhibitor aminoglutethimide), is a valuable drug for the second-line treatment of postmenopausal women with advanced breast cancer.

Complete estrogen blockade for the treatment of metastatic and early stage breast cancer.

Complete estrogen blockade has long been sought as a more effective means of controlling breast cancer compared with single agent endocrine therapy. This approach may be accomplished through the use of agents which reduce estrogen production combined with agents that prevent the activity of estrogen at the cellular level. For prostate cancer, another hormonally responsive malignancy, this approach has not been successful at improving survival compared with that achieved with single agent therapy. Preclinical information is contradictory for many promising combinations and may not reflect the true nature of in vivo interaction between agents. For premenopausal patients with metastatic breast cancer, the combination of a luteinising hormone-releasing hormone (LHRH) agonist and tamoxifen is clearly effective, but whether the combination is more effective than either single agent is still controversial. Similar response rates and overall survival were reported with goserelin or goserelin plus tamoxifen by Jonat et al. in 1 randomised, prospective study, but the addition of tamoxifen improved time to progression. A second trial comparing buserelin plus tamoxifen with either single agent reported superior efficacy in terms of response rates, disease-free survival and overall survival with combination therapy. A meta-analysis of 4 randomised trials making similar comparisons, demonstrated significant improvement in median overall survival, progression-free survival, response rate, and duration of response with the combination of a LHRH agonist (goserelin or buserelin) and tamoxifen in premenopausal breast cancer patients with metastatic disease. For postmenopausal women with metastatic breast cancer, the addition of an aromatase inhibitor to tamoxifen has yet to be prospectively compared to single agent therapy. Use of endocrine combinations in the treatment of early stage breast cancer is under investigation. Preliminary results of some of the ongoing adjuvant therapy trials indicate that the combination of a LHRH agonist and tamoxifen may have similar efficacy to cyclophosphamide, methotrexate, and fluorouracil chemotherapy in premenopausal women with estrogen receptor-positive tumour. Addition of LHRH agonist therapy in premenopausal patients with estrogen receptor-positive tumour who had maintained the ovarian function following chemotherapy [cyclophosphamide, doxorubicin (adriamycin), fluorouracil, and tamoxifen], also led to a reduction in the risk of recurrence. These studies have identified a sub-population of patients who may benefit from the addition of combination endocrine therapy. Overall, the issue is quite complex and the data from many ongoing trials are still awaited with anticipation to further delineate the role of complete estrogen deprivation in this disease.

The current status of aromatase inhibitors in the management of breast cancer.

The third generation of specific AIs have made a very exciting contribution to the management of hormone responsive breast cancer. We can now state with confidence that their role in advanced breast cancer has overtaken that of tamoxifen, which should be relegated to a second-line treatment. Indeed, as a recent publication confirmed that first-line anastrozole followed by tamoxifen is an effective treatment sequence, this sequence may be considered the best choice for treating patients with hormone receptor-positive ABC. As far as the primary disease is concerned, the ATAC data certainly suggest that there is an alternative to tamoxifen in selected postmenopausal women with hormone receptor-positive disease. With more mature follow-up the study might even show that after a passage of nearly 20 years tamoxifen has lost its lead position in the adjuvant stakes as well.

Hormonal therapy for breast cancer: focus on fulvestrant.

Fulvestrant, the first drug of the pure estrogen antagonists to be approved for clinical use, is a new therapeutic option for metastatic breast cancer. Fulvestrant offers a unique metastatic breast cancer treatment option because its mechanism of action is the destruction, rather than the blockade, of estrogen receptors. No known agonistic activity exists, limiting potential side effects and receptor exhaustion. The side effect profile of fulvestrant is related to its antiestrogen effect and includes gastrointestinal disturbance, urinary tract infection, and vaginitis. Suggestions for managing the side effects of fulvestrant are described, and a case study is provided as an illustrative aid in understanding the role of this new hormonal agent.

[Current status and prospectives of aromatase inhibitors in the treatment of advanced breast cancer]. / Stato attuale e prospettive nel trattamento del carcinoma mammario avanzato con gli inibitori dell'aromatasi.

Endocrine therapy represents one of the most effective instruments for the palliative and adjuvant treatment of breast cancer, in particular in postmenopausal patients. While tamoxifen still forms the treatment of choice during the adjuvant phase and the first-line treatment during the metastatic phase, aromatase inhibitors undoubtedly represent the treatment of choice for patients who do not respond to antiestrogen treatment. These drugs represent a heterogeneous family of compounds able to provide more or less selective inhibition of aromatases by forming an irreversible bond with the catalytic site of the enzymatic complex (type I inhibitors) or using a competitive mechanism (type II inhibitors). Among the type I drugs, 4-hydroxyandrostenedione and hexamestane are those that probably attract greatest clinical interest. These drugs can significantly reduce the circulating levels of estrone and estradiol, and have been shown to be active in 20% of patients pretreated with tamoxifen. Moreover, hexamestane was also effective in patients pretreated with type II inhibitors, of which the parent drug is aminoglutethimide. This drug is still used in the second and third-line treatment of breast cancer but, since it causes collateral effects in a substantial percentage of patients, above all when used at higher doses in combination with hydrocortisone, it will soon be replaced by second and third generation inhibitors, like letrozole, fadrozole, vorozole and anastrozole. These drugs have been shown to be significantly more active than aminoglutethimide, both in vitro and in vivo, and above all more selective. In particular, even at high doses anastrozole has not been found to interfere with steroidogenesis at a corticoadrenal level. Moreover, anastrozole has been shown to be very active even at relatively modest doses given in a single daily dose. Two recent controlled studies, including a total of over 600 patients, recently demonstrated that, if used in second line in patients who no longer responded to adjuvant or palliative tamoxifen therapy, anastrozole is just as effective but probably better tolerated than megestrol acetate. Studies are now in progress or are currently being launched to evaluate the possible value of anastrozole and other third generation inhibitors both as first-line treatment and as adjuvant treatment as an alternative or in combination with tamoxifen.

[Chemoprevention of breast cancer. Clinical trials in pharmacological prevention]. / Quimioprevención del cáncer de mama. Ensayos clínicos en la prevención farmacológica.

The following review article focuses on chemoprevention clinical trials of breast cancer. To date, SERMs (Selective Estrogen Receptor Modulators) have been the most studied drugs. Four randomized trials with tamoxifen vs. placebo have been performed and two with raloxifene are being carried out. Two tamoxifen trials showed between 30 and 50% reduction in breast cancer incidence. However, two other studies showed no statistical differences. Moreover, the real impact on mortality that these therapies could have is still unknown. This article includes a revision of trials that evaluated the relationship between daily vitamin intake and breast cancer. A follow up of these trials will give us answers about which patients will benefit from chemoprevention therapies.

[Hormone therapy of metastasizing breast carcinoma]. / Hormontherapie des metastasierenden Mammakarzinoms.

In patients with metastatic breast cancer, cure is almost always an exception, irrespective of the therapy given. Thus the preservation of the quality of life or palliation in case of symptoms must be the principal goal. Only a small group of patients with their tumour showing a highly aggressive behaviour should be considered for primary chemotherapy. Aggressive tumour growth is then characterized by negative hormonal receptors, short disease-free interval and predominant visceral tumour growth. For all other patients there is not enough advantage to justify the clearly higher toxicity of a primary chemotherapy. This majority of patients with metastatic breast cancer can profit to a higher degree from hormonal treatment. Irrespective of the type of the hormonal therapy, the response rate is positively correlated with postmenopausal status, high hormonal receptor expression, al long disease-free interval, no previous adjuvant therapy and higher age. Advantages and problems of the various forms of hormonal manipulations are discussed. The recommended sequence of therapy represents only a handrail that needs to be adjusted carefully, according to the individual situation, the needs and expectations of the patient and in due knowledge of the toxicity of each hormonal substance. Combinations of different hormonal agents do not yield an additional benefit and should therefore be dropped for a sequential approach.

[Controlled ovarian hyperstimulation (COH) and management of low-responder cases (HOO)]. / Kontrolirana ovarialna khiperstimulatsiia (COH) i povedenie pri sluchaite s nezadovolitelen ovarialen otgovor (HOO).

This paper will review the various stimulation protocols that have been attempted to improve results in low responders. Strategies have ranged from simple increasing the dose of exogenous gonadotropins, the use of adjunctive agents such as GnRH analogues and growth hormone, aromatase inhibitors and low dose aspirin. Improvements in overall responsiveness have been shown for some patients. In spite of this fact, the incremental improvement in results have generally been quite small.