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Tamoxifen is an important antiestrogen for the treatment of hormone receptor‐positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6‐mediated metabolism to 4‐OH‐solanidine (m/z 414) and 3,4‐seco‐solanidine‐3,4‐dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4‐OH‐solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4‐OH‐solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4‐OH‐solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4‐OH‐solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4‐OH‐solanidine, and SSDA are diet‐derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4‐OH‐solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6‐interacting medications. Accordingly, 4‐OH‐solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Monocytes comprise subsets of classical, intermediate and non-classical monocytes with distinct anti- or pro-tumor effects in breast cancer (BC). They are modulated by estrogen, and can contribute to BC control by endocrine therapy in preclinical models. Methods: To elucidate whether changes in monocyte subsets are associated with treatment and response, we investigated peripheral blood samples of 73 postmenopausal women with estrogen receptor (ER) positive BC, who received aromatase inhibitor therapy with or without the mucin-1 vaccine tecemotide in the ABCSG34 trial. Blood was retrieved at baseline, midterm and end of therapy, and was analyzed for the distribution and ER expression of monocyte subsets by flow cytometry. Results: When 40 healthy, age-matched women were compared with BC patients before treatment start, ER levels of monocytes did not differ, yet patients presented with a higher frequency of classical and fewer non-classical monocytes. Endocrine therapy triggered a significant increase in ER levels in all monocyte subsets, without affecting subset distribution. Vaccination had no overall impact on subset frequency and ER expression. Yet, a shift from intermediate to classical monocytes during therapy correlated with changes in plasma cytokines and chemokines and was significantly associated with low residual cancer burden in vaccinated patients. Without tecemotide, baseline ER levels in classical monocytes were significantly higher in women with good response to endocrine therapy. Conclusions: This study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination. [ABSTRACT FROM AUTHOR]

This study describes the synthesis of N5‐(4‐(1H‐benzo[d]imidazol‐2‐yl)phenyl)‐N2‐phenylpyridine‐2,5‐diamine derivatives from Orthophenylenediamine (1) and 4‐aminobenzoic acid (2) and all the synthesized chemical moieties screened against a panel of cancer cell lines resulted in the identification compound 6 a with good anti‐cancer potential and a GI50 of 2.95 μM, 3.35 μM, 2.27 μM, 8.46 nM and 1.56 μM against MDAMB‐231, MCF‐7, A‐549, NCI‐H23 and A‐498 respectively. As the second greatest cause of death globally, cancer continues to pose a serious threat to public health. An essential enzyme called aromatase catalyses the last, rate‐limiting step in the production of oestrogens. As a well‐researched endocrine therapeutic strategy, aromatase inhibitors (AIs) efficiently block the production of oestrogen, which is necessary for aromatase activity. [ABSTRACT FROM AUTHOR]

Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real‐world study aimed to compare patient‐reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate‐/high‐risk premenopausal hormone receptor (HR)‐positive breast cancer. The primary endpoint was PROs, assessed using SF‐36 and EQ‐5D‐5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical (p = 0.034) and mental health (p = 0.009) dimensions of SF‐36 and lower anxiety/depression (AD) scores (p = 0.038) in EQ‐5D‐5L compared to AI group. The estimated 5‐ and 8‐year disease‐free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% (p = 0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening (p < 0.001) and a lower occurrence of morning stiffness (p < 0.001) in the toremifene compared to the AI group. Premenopausal HR‐positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles. [ABSTRACT FROM AUTHOR]

Background Despite the wide use of a 3-month gonadotropin-releasing hormone (GnRH) agonist for ovarian function suppression in premenopausal breast cancer patients, it remains unclear whether it is as effective and safe as a 1-month GnRH agonist regimen when combined with selective estrogen receptor modulators or aromatase inhibitors, especially in younger patients. Methods This retrospective cohort study included 1109 premenopausal hormone receptor–positive breast cancer patients treated with GnRH agonist plus selective estrogen receptor modulator or aromatase inhibitor. The estradiol (E2) inhibition rate within 1-24 months after treatment with 1-month or 3-month GnRH agonist in cohorts and different subgroups was analyzed. Results Following 1:1 propensity score matching, 950 patients with a mean age of 39 years and a median follow-up of 46 months were included. Both the 1-month and 3-month groups achieved more than 90% E2 inhibition within 24 months (94.53% vs 92.84%, with a 95% confidence interval for the difference ranging from −4.78% to 1.41%), confirming the noninferiority of 3-month GnRH agonist. Both 1-month and 3-month GnRH agonist rapidly and consistently reduced E2 levels. Of the patients, 60 (6.3%) experienced incomplete ovarian function suppression, with similar rates in the 1-month and 3-month groups (5.5% vs 7.2%). Incomplete ovarian function suppression mainly occurred within the first 12 months, with age younger than 40 years and no prior chemotherapy being the risk factors. Similar disease-free survival and overall survival were found in the 1-month and 3-month groups and in patients with complete and incomplete ovarian function suppression (P  >  .05). Conclusions The ovarian function suppression with 3-month GnRH agonist was not inferior to that with 1-month GnRH agonist, regardless of age or combination with a selective estrogen receptor modulator or an aromatase inhibitor. [ABSTRACT FROM AUTHOR]

The mechanisms underlying breast cancer brain metastasis (BCBM) development are complex, and its clinical presentation varies depending on the number, location, and size of brain metastases. Common symptoms include headache, neurologic deficits, and seizures. Diagnosis of BCBM typically relies on neuroimaging techniques, such as magnetic resonance imaging and computed tomography scans. Local therapies, such as surgery and stereotactic radiosurgery, can be used to control tumor growth and relieve symptoms. Whole-brain radiotherapy has been a mainstay of treatment for BCBM, but its use has been associated with cognitive decline. Systemic therapy with chemotherapy and targeted agents plays an increasingly important role in the management of BCBM. Novel agents, such as human epidermal growth factor receptor 2 (HER2)–targeted therapies and tyrosine kinase inhibitors, have shown promising results in improving survival for patients with HER2-positive and triple-negative BCBM. This comprehensive review synthesizes current knowledge, clinical insights, and evolving paradigms to provide a robust understanding and roadmap for optimizing the diagnosis and management of BCBM. Improved Management of BCBM through Multi-Disciplinary Approaches, Leads to Enhanced Patient Outcomes [ABSTRACT FROM AUTHOR]

Neuroestrogens locally synthesized in the brain are known to play a role in sexual behaviors. However, the question of whether neuroestrogens are involved in the regulation of the gonadotropin‐releasing hormone (GnRH) release is just emerging. Because previous studies in this lab indicate that neuroestradiol is also important for the pulsatile release as well as the surge release of GnRH in female rhesus monkeys, in the present study, we examined whether neuroestradiol plays a role in the estrogen‐induced LH surge in orchidectomized (ORX) male rhesus monkeys. Unlike in rodents, it is known that a high dose of estrogen treatment can result in the LH surge in ORX male rhesus monkeys. Results that the administration of the aromatase inhibitor, letrozole, failed to attenuate the estrogen‐induced LH surge, suggest that unlike in ovariectomized females, neuroestrogens do not play a role in the LH surge experimentally induced by the exogenous estrogen treatment in ORX male monkeys. [ABSTRACT FROM AUTHOR]

Context Insufficient efficacy and safety data for off-label use of aromatase inhibitors to augment height in boys with short stature. Objective To compare anastrozole and letrozole in treatment of idiopathic short stature in pubertal boys. Design Open-label trial with 2 treatment arms. Setting Pediatric Endocrine Clinic at Stanford. Participants A total of 79 pubertal males ≥10 years with bone age (BA) ≤ 14 years, predicted adult height (PAH) < 5th percentile or >10 cm below mid-parental height. Intervention Anastrozole 1.0 mg or letrozole 2.5 mg daily for up to 3 years. Main Outcome Measures Annual hormone levels and growth parameters during treatment and a year posttherapy; annual BA and PAH (primary outcome measure); spine x-rays and dual energy X-ray absorptiometry at baseline and 2 years. Results Compared with anastrozole (n = 35), letrozole (n = 30) resulted in higher testosterone levels, lower estradiol and IGF-1 levels, and slower growth velocity and BA advance. The PAH increase observed at year 1 in both groups did not persist at years 2 and 3. Change in PAH from baseline was not different between treatment groups. In groups combined, PAH gain over 3 years vs baseline was +1.3 cm (P =.043) in linear mixed models. Conclusion Letrozole caused greater deviations than anastrozole in hormone levels, growth velocity, and BA advancement, but no group differences in PAH or side effects were found. Change in PAH after 2 to 3 years of treatment was minimal. The efficacy of AI as monotherapy for height augmentation in pubertal boys with idiopathic short stature may be limited, and safety remains an issue. [ABSTRACT FROM AUTHOR]

A 33-year-old young woman with a rare female appendage tumor of suspected Wolffian origin was initially diagnosed with a benign lesion after the resection of a tubal lesion due to the benign cytomorphology of the tumor tissue. However, 1 year after surgery, she was diagnosed with stage IV fallopian tube cancer due to a recurrence, which presented with substantial ascites and invasion of multiple organs, including the bilateral ovaries, intestines, pelvic peritoneum, greater omentum, and appendix. After tumor cytoreduction, the patient responded well to treatment, which included a regimen of platinum-based drugs combined with docetaxel, aromatase inhibitors such as letrozole, antihormonal therapy, and targeted therapy with bevacizumab. [ABSTRACT FROM AUTHOR]

The present study details the design, synthesis, and bio-evaluation of indoles 3-16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS) with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3-16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7,12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids' 12and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8-16, highlighting their potential as therapeutic agents with reduced toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy is the standard of care for locally advanced breast cancer; however, it is less effective in hormone receptor (HR)-positive tumors. Therefore, we aimed to evaluate the safety and efficacy of adding an aromatase inhibitor to standard neoadjuvant chemotherapy in patients with stage II or stage III HR-positive, HER2-negative breast cancer. Adding letrozole to standard neoadjuvant chemotherapy did not significantly increase the pathologic complete response (pCR) rate; however, it enhanced the overall response rate with acceptable safety. Further research is necessary to determine the optimal neoadjuvant therapy for HR-positive, HER2-negative breast cancer to address the ongoing unmet need compared with recent advances in clinical outcomes observed in HER2-positive and triple-negative subtypes. The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33–63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo–endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype. [ABSTRACT FROM AUTHOR]

Background: Premenopausal, high-risk, hormone receptor-positive breast cancer patients are often treated with ovarian suppression in combination with aromatase inhibitors (AI). This combination has important adverse effects, particularly in sexual function, such as vaginal dryness and loss of libido. There is no effective therapy for reduced sexual function in this setting. Our study aimed to determine the efficacy and safety, particularly regarding sexual function, of a low-dose, topical testosterone gel administration. Methods: This is a pilot, single-center study, designed to evaluate the efficacy of topical testosterone gel (3 mg/day) in improving sexual function in 29 premenopausal patients on ovarian suppression in combination with an AI. The primary safety endpoint was to assess serum estradiol elevation. The primary efficacy endpoint was sexual function improvement, assessed by the Female Sexual Function Index questionnaire. Results: We report the results on 29 patients. Twenty-two patients (75%) completed the 3-month treatment, and seven discontinued treatment before completion, mostly due to logistical difficulties related to the COVID-19 pandemic. All patients maintained the value of baseline mass spectrometry assay for estradiol of less than 2.7 pg/mL during the undertaken measurements. We observed a significant improvement in Female Sexual Function Index measures over the visits, with an increase from a mean of 11.7 at baseline to 19.1 in the third month (p < 0.001), with the greatest improvement observed between the second and third months. Conclusions: Our findings suggest that topical testosterone seems to be safe and may be effective in improving sexual function in patients on ovarian suppression and AI. Trial registration: The project was submitted and approved through the hospital's SGPP platform in 11/26/2019 (Project No. SGPP 393819) and CAAE (Research Ethics Committee) (CAAE No 25609719.5.0000.007). [ABSTRACT FROM AUTHOR]

Background: Aromatase inhibitors improve male fertility by modifying the hormonal control of spermatogenesis. The present study aimed to investigate the effects of oral administration of letrozole on testosterone and estradiol concentrations and their ratios in blood serum, seminal plasma, prostatic fluid, sperm quality in fresh semen, and prostate gland dimensions. Seven adult male intact mixed-breed dogs were selected. The animals received letrozole (72 µg/kg, PO) daily for four weeks. Blood samplings and semen collections were carried out on days 0 (control), 14 (treatment), 28 (treatment), and 42 (post-treatment). Results: Our results showed that letrozole administration resulted in a 4.3 fold significant increase in serum, seminal plasma, and prostatic fluid testosterone levels after 14 days. This remained high until the end of the study. Serum and prostatic fluid estradiol levels did not change significantly over the study period. However, the seminal plasma estradiol level showed a significant increase on day 14. The estradiol: testosterone ratio was significantly reduced on day 14 in serum, seminal plasma, and prostatic fluid samples. Letrozole significantly improved the ejaculated spermatozoa viability and concentration after 28 days of oral administration. However, the sperm plasma membrane functional integrity and kinematic parameters were not significantly affected by the treatment. Transabdominal ultrasound examination revealed a significant increase in the height, width, and volume of the prostate gland after 28 days of treatment. Conclusions: According to the present research, oral administration of letrozole for 28 days affects local and systemic sex hormone balance leading to an improvement of the ejaculated canine spermatozoa viability and concentration concurrent with an increase in the prostate gland dimensions. [ABSTRACT FROM AUTHOR]

Primary endometrial squamous cell carcinoma (PESCC) is a rare malignant tumor. To investigate the clinical and pathological features of PESCC, two cases of PESCC in Fujian Maternal and Child Health Hospital were retrospectively studied and the literatures were reviewed. Both of the two cases were menopausal women aged 57-62 years, clinically presenting with "vaginal discharge". Case 1 was a non-keratinising squamous cell carcinoma with high-risk HPV infection. Tumor infiltrated in deep myometrium with multifocal intravascular thrombus and macro metastases to one pelvic lymph node (1/15) and abdominal aortic lymph node (1/1). Lung metastasis occurred 36 months after the surgery. After surgical resection and without postoperative supplemental therapy, the patient remained tumor-free for 110 months to date. Case 2 had a history of breast cancer for 5 years and long-term intake of aromatase inhibitor drugs without HPV infection. It was a keratinized squamous cell carcinoma. Tumor also infiltrated in deep myometrium with multifocal intravascular thrombus and one pelvic lymph node metastasis (1/18), However, no metastasis was seen elsewhere. To date, the patient survived for 16 months without tumor after surgery. Both of the two cases expressed squamous epithelial markers P40, P63, and CK5/6, but neither expressed PAX8 or PR. Case 1 had diffuse expression of P16, wild-type P53, and ER-negative. Case 2 had negative P16, mutant P53, and focal positive ER. PESCC is often associated with HPV infection and low estrogen levels. However, studies in the literatures have found that P16 expression is not always consistent with HPV infection, indicating that PESCC cannot be easily classified as HPV-associated or non-dependent like cervical cancer. There are two main patterns of P16 and P53 expression, P16- positive/P53 wild-type and P16-negative/P53-mutant, but no positive expression of both has been seen so far. It is worth noting that we reported the second case of PESCC with a history of breast cancer, where the patient had been taking the oral aromatase inhibitor drug (exemestane) for a long period of time to reduce the estrogen level, indicating the low estrogen level may be also a key factor in the pathogenesis of PESCC. [ABSTRACT FROM AUTHOR]

Background: Acupuncture therapy shows promise in managing aromatase inhibitor-induced arthralgia (AIA) among breast cancer patients. An umbrella review synthesizes findings from systematic reviews and meta-analyses (SRs/MAs) to assess its effectiveness. Summary: This umbrella review aimed to evaluate the effectiveness of acupuncture therapy in treating AIA among breast cancer patients by analyzing existing evidence from SRs/MAs. Key Messages: Six SRs/MAs were analyzed, revealing shortcomings in reporting quality, methodological quality, and evidence quality assessment. Comprehensive searches across eight electronic databases were conducted. PRISMA, AMSTAR 2, and GRADE were utilized to assess reporting, methodological quality, and evidence quality, respectively. Despite methodological shortcomings, a recent meta-subgroup analysis suggests the efficacy of acupuncture therapy for AIA patients, recommending a 10-session treatment course. Conclusion: Acupuncture is identified as a secure and effective remedy for AIA sufferers, yet further high-quality research is needed to strengthen the evidence base and endorse acupuncture as a viable treatment option. [ABSTRACT FROM AUTHOR]

Background: Although there are a growing number of studies investigating the benefits of music therapy interventions with patients diagnosed with cancer, few studies have taken an approach that specifically examines indices of perceived well-being in women with breast cancer. Overcoming these challenges can be an important step in the recovery process. Purpose: The purpose of our study was to know the positive influence of responsive music therapy through gong sounds, emitted live, on different areas of well-being of women with breast cancer. Methods: Four individual sessions of responsive music therapy with live gong sounds were conducted in which three women (M = 54; SD = 5.57) participated both in the music therapy program and in the completion of the Functional Assessment of Cancer Therapy – Breast (FACT-B) and a semi-structured interview with ad hoc designed questions about perception of qualitative aspects. Results: The results showed that the music therapy sessions significantly improved, p =.043 < 0.05, various domains of perceived well-being in women with breast cancer. Discussion: This article highlights several key benefits associated with music therapy and various indices of well-being in women with breast cancer, identifies the limitations of the study, and discusses the findings. It is considered necessary to replicate this practice in future studies that include a larger sample and age range over longer follow-up periods. Translation for Health Education Practice: The text highlights the importance of considering music therapy as a complementary intervention in comprehensive cancer care programs, which may be relevant to health educators when considering intervention and support approaches for cancer patients. Health education interventions targeting the enhancement of cancer patients' well-being should incorporate music therapy techniques. [ABSTRACT FROM AUTHOR]

The key step in the biosynthesis of estrogen is the enzyme activity of aromatase. Several malignancies, including breast cancer, have been linked to the initiation and progression of estrogen overexpression. Exemestane, Arimidex and Femara are the most common aromatase inhibitors used to treat hormone-dependent breast cancers. Drug resistance and side effects are commonly associated with these treatments. The purpose of this in silico study was to list the chemical compounds of Juniperus procera that have been published in scientific papers. The second goal was to evaluate the inhibitory activity of 124 phytochemicals of Juniperus procera compared to known aromatase inhibitors such as Exemestane, Arimidex and Femara. The 3D structure of aromatase (PDB id: 3s7s) employed for docking studies using AutoDock Tools as well as normal mode analysis studies utilizing the NMSim web server. Juniperolide, Kaurenoic acid and Isocupressic acid were identified as competitive aromatase inhibitors compared to FDA approved anti-cancer drugs, specifically Exemestane, Arimidex and Femara. The stability of the ligand–protein interface was studied to support the docking findings. To our knowledge, this is the first study that investigates the possible inhibition roles of some compounds of Juniperus procera on the aromatase enzyme. [ABSTRACT FROM AUTHOR]

Introduction: The aromatase enzyme plays an important role in the progress of hormonedependent breast cancer, especially in estrogen receptor-positive (ER+) breast cancers. In case of postmenopausal women, the aromatization of androstenedione to estrone in adipose tissue is the most important source of estrogen. Generally 60%-75% of pre- and post-menopausal women suffer from estrogendependent breast cancer, and thus suppressing estrogen has been recognized to be a successful therapy. Hence, to limit the stimulation of estrogen, aromatase inhibitors (AIs) are used in the second-line treatment of breast cancer. Methods: The present computational study employed an in silico approach in the identification of natural actives targeting the aromatase enzyme from a structurally diverse set of natural products. Molecular docking, QSAR studies and pharmacophore modeling were carried out using the VLife Molecular Design Suite (version 4.6). The stability of the compounds was confirmed by molecular dynamics. Results: From molecular docking and analysis of interactions with the amino acid residues of the binding cavity, it was found that the amino acid residues interacting with the non-steroidal inhibitors exhibited p-stacking interactions with PHE134, PHE 221, and TRP 224, while the steroidal drug exemestane lacked p-stacking interactions. QSAR studies were performed using the flavonoid compounds, in order to identify the structural functionalities needed to improve the anti-breast cancer activity. Molecular dynamics of the screened hits confirmed the stability of compounds with the target in the binding cavity. Moreover, pharmacophore modelling presented the pharmacophoric features of the selected scaffolds for aromatase inhibitory activity. Conclusion: The results presented 23 hit compounds that can be developed as anti-breast cancer modulating agents in the near future. Additionally, anthraquinone compounds with minor structural modification can also serve to be potential aromatase inhibitors. The in silico protocol utilised can be useful in the drug discovery process for development of new leads from structurally diverse set of natural products that are comparable to the drugs used clinically in breast cancer therapy. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments? SUMMARY ANSWER Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels. WHAT IS KNOWN ALREADY PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses. LET PCOS-like females also have increased hypothalamic kisspeptin neuronal activation which may drive their hyperactive LH secretion and hyperandrogenemia, but this has not been tested. STUDY DESIGN, SIZE, DURATION Transgenic KissCRE+/hM4Di female mice or littermates Cre− controls were treated with placebo, or chronic LET (50 µg/day) to induce a PCOS-like phenotype, followed by acute (once) or chronic (2 weeks) clozapine- N -oxide (CNO) exposure to chemogenetically inhibit kisspeptin cells (n = 6 to 10 mice/group). PARTICIPANTS/MATERIALS, SETTING, METHODS Key endocrine measures, including in vivo LH pulse secretion patterns and circulating testosterone levels, were assessed before and after selective kisspeptin neuron inhibition and compared between PCOS groups and healthy controls. Alterations in body weights were measured and pituitary and ovarian gene expression was determined by qRT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE Acute targeted inhibition of kisspeptin neurons in PCOS mice successfully lowered the abnormally hyperactive LH pulse secretion (P  < 0.05). Likewise, chronic selective suppression of kisspeptin neuron activity reversed the previously high LH and testosterone levels (P  < 0.05) down to healthy control levels and rescued reproductive gene expression (P  < 0. 05). LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Ovarian morphology was not assessed in this study. Additionally, mouse models can offer mechanistic insights into neuroendocrine processes in PCOS-like conditions but may not perfectly mirror PCOS in women. WIDER IMPLICATIONS OF THE FINDINGS These data support the hypothesis that overactive kisspeptin neurons can drive neuroendocrine PCOS-like impairments, and this may occur in PCOS women. Our findings complement recent clinical investigations using NKB receptor antagonists to lower LH in PCOS women and suggest that pharmacological dose-dependent modulation of kisspeptin neuron activity may be a valuable future therapeutic target to clinically treat hyperandrogenism and lower elevated LH in PCOS women. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by NIH grants R01 HD111650, R01 HD090161, R01 HD100580, P50 HD012303, R01 AG078185, and NIH R24 HD102061, and a pilot project award from the British Society for Neuroendocrinology. There are no competing interests. [ABSTRACT FROM AUTHOR]

Background Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2−) early breast cancer (EBC) with high-risk clinicopathological features face an increased risk of recurrence. This study explored the evolving treatment landscape and clinical outcomes in patients with EBC using a nationwide database. Patients and Methods The study cohort comprised HR+/HER2−, stages 1-3, patients with EBC who underwent surgery and received adjuvant endocrine therapy (AET) from January 2013 to March 2021. High-risk patients were defined by ≥4 positive axillary lymph nodes, or 1-3 positive lymph node(s) with at least one high-risk feature (histologic grade 3, tumor size ≥5 cm, or Ki-67 ≥20%). A low-risk cohort included patients not meeting the criteria. Survival analysis was conducted with a cutoff of September 2021. Results The study included 4088 eligible patients (1310 high-risk patients and 2778 low-risk patients). High-risk patients were more likely to receive adjuvant chemotherapy and radiotherapy compared to low-risk patients. From 2013 to 2021, an increasing proportion of patients received aromatase inhibitors and ovarian function suppression as part of their AET. The 2-, 5-, and 7-year invasive disease-free survival for high-risk cohort were 90.67%, 75.26%, and 57.10%, respectively, these rates were notably higher for low-risk cohort at 97.14%, 89.85%, and 84.83%. High-risk patients demonstrated a higher risk of recurrence or death compared with low-risk patients (hazard ratio, 2.38; 95% CI, 1.82-3.12). Conclusion In the setting of standard or even intensive AET, patients with EBC with high-risk features still present high recurrence risk, highlighting the urgent need for innovative adjuvant treatment strategies. [ABSTRACT FROM AUTHOR]

Background/Aim: Endocrine therapy is the standard treatment for hormone receptor-positive (HR+) breast cancer (BC). Yet, it is accompanied by treatment-related toxicities, leading to poor treatment adherence, high relapse, and low rates of survival. While pharmacogenomic variants have the potential to guide personalized treatment, their predictive value is inconsistent across published studies. Materials and Methods: To systematically assess the literature's current landscape of pharmacogenomics of endocrine therapy-related adverse drug effects, systematic searches in MEDLINE, Embase, Cochrane CENTRAL, Google Scholar and PharmGKB databases were conducted. Results: We identified 87 articles. Substantial heterogeneity and variability in pharmacogenomic effects were evident across studies, with many using data from the same cohorts and predominantly focusing on the Caucasian population and postmenopausal women. Meta-analyses revealed Factor V Leiden mutation as a predictor of thromboembolic events in tamoxifen-treated women (p<0.0001). Meta-analyses also found that rs7984870 and rs2234693 were associated with musculoskeletal toxicities in postmenopausal women receiving aromatase inhibitors (p<0.0001 and p<0.0001, respectively). Conclusion: Overall, the current body of evidence regarding the potential role of pharmacogenomics in endocrine therapy-related toxicity in BC remains largely inconclusive. Key concerns include the heterogeneity in toxicity definitions, lack of consideration for genotype-treatment interactions, and the failure to account for multiple testing. The review underscores the necessity for larger and well-designed studies, particularly with the inclusion of premenopausal women and non-Caucasian populations. [ABSTRACT FROM AUTHOR]

Purpose: Aromatase inhibitors (AI) block estrogen synthesis and are used as long-term adjuvant treatment for breast cancer in postmenopausal women. AI use can be associated with weight gain that can lead to increased cardiometabolic risk. The response to anti-obesity medications (AOM) in patients using AI has yet to be studied. We sought to investigate weight loss outcomes of AOM in patients taking AI for breast cancer treatment. Methods: This is a matched retrospective cohort study of breast cancer survivors on AI using AOM (AOM/AI group). We compared their weight loss outcomes with a group of female patients with obesity, without a history of breast cancer or AI use, on AOM (AOM group). The primary endpoint was total body weight loss percentage (TBWL %) at the last follow-up. We performed mixed linear regression models, including diabetes status at baseline, to assess associations between use of AOM with/without AI with total body weight loss percentage (TBWL%). Results: We included 124 patients: 62 in the AOM/AI group (63.6 ± 10 years, body mass index [BMI] 34.3 ± 7.1 kg/m2) and 62 in the AOM group (62.8 ± 9.9 years, BMI 34.6 ± 6.5 kg/m2). The mean time of follow up was 9.3 ± 3.5 months, with no differences among the two groups. The AOM/AI group had a lower TBWL% compared to the AOM group at the last follow-up −5.3 ± 5.0 vs. −8.2 ± 6.3 (p = 0.005). The results remained significant after adjusting for diabetes status (p = 0.0002). At 12 months, the AOM/AI group had a lower TBWL% compared to the AOM group 6.4 ± 0.8% vs. 9.8 ± 0.9% (p = 0.04). The percentage of patients achieving ≥ 5%, ≥ 10%, and ≥ 15% of weight loss at 12 months was greater in the AOM compared to the AOM/AI group. Although the weight loss response was suboptimal, patients in the AOM/AI group had improvement in fasting glucose, glycated hemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol. Conclusions: The use of AI in breast cancer survivors is associated with less weight loss response to AOM compared to patients without breast cancer history and who do not take AI. Studies are needed to assess the mechanisms behind the differential weight loss response to AOM in women taking AI. [ABSTRACT FROM AUTHOR]

Purpose: Trials demonstrating benefits of tamoxifen for women with ductal carcinoma in situ (DCIS) were published > 20 years ago; yet subsequent uptake of endocrine therapy was low. We estimated endocrine therapy initiation in women with DCIS between 2001 and 2018 in a community setting, reflecting more recent years of diagnosis than previous studies. Methods: This retrospective cohort included adult females ≥ 20 years diagnosed with first primary DCIS between 2001 and 2018, followed through 2019, and enrolled in one of three U.S. integrated healthcare systems. We collected data on endocrine therapy dispensings (tamoxifen, aromatase inhibitors [AIs]) from electronic pharmacy records within 12 months after DCIS diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated endocrine therapy initiation rates over time and by patient, tumor (including estrogen receptor [ER] status), and treatment characteristics. Results: Among 2020 women with DCIS, 587 (29%) initiated endocrine therapy within 12 months after diagnosis (36% among 1208 women with ER-positive DCIS). Among women who used endocrine therapy, 506 (86%) initiated tamoxifen and 81 (14%) initiated AIs. Age-adjusted endocrine therapy initiation declined from 34 to 21% between 2001 and 2017; between 2015 and 2018, AI use increased from 8 to 35%. Women less likely to initiate endocrine therapy were ER-negative or had borderline/unknown or no ER test results, ≥ 65 years at diagnosis, Black, and received no radiotherapy. Conclusion: One-third of women diagnosed with DCIS initiated endocrine therapy, and use decreased over time. Understanding why women eligible for endocrine therapy do not initiate is important to maximizing disease-free survival following DCIS diagnosis. [ABSTRACT FROM AUTHOR]

Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia's severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia. Here, the authors provide evidence that SARS-CoV-2 N protein leads to autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inducing DNA damage and proteotoxic stress, eventually causing pneumonia. The small-molecule drug PJ34 or anastrozole alleviates N protein-induced pneumonia. [ABSTRACT FROM AUTHOR]

Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: A series of 4-amino-5-((2,4-substituted phenoxy)methyl)-4H-1,2,4-triazole-3-thiol derivatives (Ia–Ib) were synthesized and tested as aromatase enzyme inhibitor. Methods: 4-Amino-5-((2,4-substituted phenoxy)methyl)-4H-1,2,4-triazole-3-thiol derivatives (Ia–Ib) were synthesized via fusion of substituted phenoxycarboxylic acid derivatives with thiocarbohydrazide. Three series of the newly title compounds were prepared by reaction of (Ia–Ib) with aromatic acid derivatives in presence of POCl3 to give [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (IIa–IIh) or by reaction with phenacyl bromide derivatives in presence of sodium acetate to produce [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives (IIIa–IIIh). Moreover, (Ia–Ib) were used as a precursor for synthesizing of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives (Va–Vd) by reaction with dibromochalcone compounds (IVa–IVb) in presence of triethylamine. The aromatase activities of the newly created compounds were examined. Results and Discussion: Seven triazoles were shown to have significant aromatase inhibitory activity (IC50 = 0.07–1.92 µM). It's interesting to note that analogue (Vb), which substituted a p-chlorophenyl ring at the triazole ring, had the greatest aromatase-inhibitory action (IC50 = 70 µM). Conclusions: The result of the present work indicated that compound (Vb) would be valuable as a potent anticancer agent. Moreover, docking study has been done into aromatase cytochrome P450 enzyme active site (PDB ID: 3EQM) for lead optimization of the aforementioned compounds as prospective tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Testosterone deficiency (TD) is relatively common in aging men, affecting around 2% of the general population. Testosterone replacement therapy (TRT) represents the most common medical approach for subjects who are not interested in fathering. Areas covered: This review summarizes advances in TRT, including approved or non-approved pharmacological options to overcome TD. When possible, a meta-analytic approach was applied to minimize subjective and biased interpretations of the available data. Expert opinion: During the last decade, several new TRT formulations have been introduced on the market, including oral, transdermal, and parenteral formulations. Possible advantages and limitations have been discussed appropriately. Anti-estrogens, including selective estrogen modulators or aromatase inhibitors still represent further possible off-label options. However, long-term side effects on sexual function and bone parameters constitute major limitations. Glucagon-like peptide 1 analogues can be an alternative option in particular for massive obesity-associated TD. Weight loss obtained through lifestyle modifications including diet and physical exercise should be encouraged in all overweight and obese patients. A combination of TRT and lifestyle changes can be considered in those subjects in whom a reversal of the condition cannot be expected in a reasonable time frame. [ABSTRACT FROM AUTHOR]

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

Copyright of Chinese Journal of Osteoporosis is the property of Chinese Journal of Osteoporosis and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: We aimed to evaluate cardiac safety profile of ribociclib with 24-h rhythm Holter ECG. Material and method: Forty-two female metastatic breast cancer patients were included in the study. Rhythm Holter ECG was performed before starting treatment with ribociclib and after 3 months of the treatment initiation. Results: The mean age of the patients was 56.36 ± 12.73. 52.4% (n = 22) of the patients were using ribociclib in combination with fulvestrant and 47.6% (n = 20) with aromatase inhibitors. None of the patients developed cardiotoxicity. When the rhythm Holter results before and in third month of the treatment were compared, there was no statistically significant difference. Conclusion: This is the first study evaluating effects of ribociclib treatment on cardiac rhythm with Holter ECG. The findings suggested ribociclib has a low risk of causing early cardiotoxicity. [ABSTRACT FROM AUTHOR]

Background Bone health management in premenopausal women with breast cancer (BC) under hormone-deprivation therapies (HDTs) is often challenging, and the effectiveness of bone-active drugs is still unknown. Methods This retrospective multicenter study included 306 premenopausal women with early BC undergoing HDTs. Bone mineral density (BMD) and morphometric vertebral fractures (VFs) were assessed 12 months after HDT initiation and then after at least 24 months. Results After initial assessment, bone-active drugs were prescribed in 77.5% of women (151 denosumab 60 mg/6 months, 86 bisphosphonates). After 47.0 ± 20.1 months, new VFs were found in 16 women (5.2%). Vertebral fracture risk was significantly associated with obesity (odds ratio [OR] 3.87, P =.028), family history of hip fractures or VFs (OR 3.21, P =.040], chemotherapy-induced menopause (OR 6.48, P <.001), preexisting VFs (OR 25.36, P <.001), baseline T -score less than or equal to −2.5 standard deviation (SD) at any skeletal site (OR 4.14, P =.036), and changes at lumbar and total hip BMD (OR 0.94, P =.038 and OR 0.88, P <.001, respectively). New VFs occurred more frequently in women untreated compared to those treated with bone-active drugs (14/69, 20.8% vs 2/237, 0.8%; P <.001) and the anti-fracture effectiveness remained significant after correction for BMI (OR 0.03; P <.001), family history of fractures (OR 0.03; P <.001), chemotherapy-induced menopause (OR 0.04; P <.001), and preexisting VFs (OR 0.01; P <.001). Conclusions Premenopausal women under HDTs are at high risk of VFs in relationship with high BMI, densitometric diagnosis of osteoporosis, preexisting VFs, and family history of osteoporotic fractures. Vertebral fractures in this setting might be effectively prevented by bisphosphonates or denosumab. [ABSTRACT FROM AUTHOR]

Background: Male factor infertility affect up to 50% of couples unable to conceive spontaneously. Several non-hormonal pharmacological treatments have been proposed to boost spermatogenesis and increase chances of conception in men with infertility. Still, no clear evidence exists on the most effective treatment strategy. Objective: We aimed to compare the effectiveness of non-hormonal pharmacological treatment options for men with infertility using a systematic review and network meta-analysis. Methods: We searched MEDLINE, EMBASE, and CENTRAL until October 2023 for randomised/quasi-randomised trials that evaluated any non-hormonal pharmacological treatment options for men with idiopathic semen abnormalities or those with hypogonadism. We performed pairwise and network meta-analyses using a random effect model. We assessed risk of bias, heterogeneity, and network inconsistency. We calculated the mean rank and the surface under the cumulative ranking curve (SUCRA) for each intervention the maximum likelihood to achieve each of reported outcomes. We reported primarily on sperm concentration and other important semen and biochemical outcomes using standardised mean difference (SMD) and 95% confidence-intervals(CI). Results: We included 14 randomised trials evaluating four treatments (Clomiphene citrate, Tamoxifen, Aromatase inhibitors, anti-oxidants) and their combinations in 1342 men. The overall quality of included trials was low. Sperm concentration improved with clomiphene compared to anti-oxidants (SMD 2.15, 95%CI 0.78–3.52), aromatase inhibitor (SMD 2.93, 95%CI 1.23–4.62), tamoxifen (SMD − 1.96, 95%CI -3.57; -0.36) but not compared to placebo (SMD − 1.53, 95%CI -3.52- 0.47). Clomiphene had the highest likelihood to achieve the maximum change in sperm concentration (SUCRA 97.4). All treatments showed similar effect for sperm motility, semen volume, and normal sperm morphology. FSH levels showed significant improvement with clomiphene vs.anti-oxidant (SMD 1.48, 95%CI 0.44–2.51) but not compared to placebo. The evidence networks for LH and testosterone suffered from significant inconsistency (p = 0.01) with similar trend of improvement with clomiphene compared to other treatments but not compared to placebo. Conclusion: There is insufficient evidence to support the routine use of Clomiphene, tamoxifen, and aromatase inhibitors to optimise semen parameters in men with infertility. Future randomised trials are needed to confirm the efficacy of clomiphene in improving fertility outcomes in men. PROSPERO: CRD42023430179. [ABSTRACT FROM AUTHOR]

Purpose: To summarize the findings of relevant randomized controlled trials (RCTs) and conduct a meta-analysis to investigate the potential effect of aromatase inhibitors on preventing moderate to severe ovarian hyperstimulation syndrome (OHSS) in infertile women undergoing in vitro fertilization (IVF). Methods: We searched for relevant RCTs in electronic databases, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (from inception to August 2023). In addition, we manually searched the related reviews and reference lists of included studies for further relevant studies. We included RCTs where aromatase inhibitors prescribed either during controlled ovarian stimulation (COS) or in early luteal phase. The meta-analysis was performed using RevMan 5.4.1 software. The primary outcome was the incidence of moderate to severe OHSS. A descriptive analysis was conducted in cases where a meta-analysis was not feasible due to heterogeneity or lack of comparable data. Results: 2858 records were retrieved and 12 RCTs were finally included. Letrozole was administered in the treatment group during COS in seven RCTs, whereas in the early luteal phase in five RCTs. Compared with the control group, the risk of moderate to severe OHSS significantly reduced by 55% in the letrozole group (RR 0.45, 95% CI 0.32 to 0.64, I2 = 0%, 5 RCTs, 494 patients). Moreover, serum estradiol (E2) levels on hCG trigger day significantly decreased with the administration of letrozole during COS (MD -847.23, 95% CI -1398.00 to -296.47, I2 = 93%, 5 RCTs, 374 patients). And serum E2 levels on the 4th, 5th and 7th to 10th day after hCG trigger were also significantly lower than those in the control group when letrozole was administered in the early luteal phase. Conclusions: Patients with high risk of OHSS probably benefit from letrozole, which has been revealed to reduce the incidence of moderate to severe OHSS by this systematic review. However, the very limited number of participants and the quality of the included studies does not allow to recommend letrozole for the prevention of severe OHSS. [ABSTRACT FROM AUTHOR]

Throughout history, humans have heavily relied on plants for both nourishment and the treatment of diseases. Breast cancer chemotherapies are expensive, have side effects, and may develop resistant cells. This shows the need for natural therapies to reduce the side effects of pharmacological remedies. Our objective was to isolate phytochemicals from the ethanol extract of the Eugenia uniflora plant. Another objective was to assess the antioxidant activity of the crude ethanolic extract of E. uniflora leaves and predict the drug-likeness, pharmacokinetics, and binding potentials of the identified phytochemicals as anti-breast cancer agents. From the results, fifteen phytochemicals were isolated and identified. The average total phenolic content (TPC), total flavonoid content (TFC), radical scavenging activity (DPPH), and ferric reducing antioxidant power (FRAP) values for the ethanol extract were 119.5 mg GAE/g, 141.16 mg GAE/g, 37.8 µg/mL, and 7.2 mmol/g, respectively. The chemical composition revealed 15 compounds: 3-Undecene, Acetic acid, Benzofuran, Hydroquinone, alpha-L-Galactopyranose, Methyl hexofuranoside, Nonadecanoic acid, 10-Octadecenoic acid, 2-Nonen-1-ol, Z-8-Methyl-9-tetradecenoic, 10-Undecenal, 2-Octylcyclopropene-1-heptanol, 1,5-Cyclododecadiene, Allantoic acid, and Stearic acid hydrazide. The drug-likeness and ADME properties of the fifteen identified compounds revealed non-violation of Lipinski's rules of five requirements. The docking screening of the fifteen identified phytochemicals with the human placental aromatase target revealed Stearic acid hydrazide, with the highest binding affinity of -7.86 kcal/mol, which can serve as a competitive aromatase inhibitor. The in-silico study gave a high probability that some of these compounds could be used as aromatase inhibitors and thus play a role in treating breast cancer. As far as we are aware, there has been no prior research conducted on the potential inhibitory effects of certain compounds found in E. uniflora on the aromatase enzyme. [ABSTRACT FROM AUTHOR]

Key Clinical Message: There is no consensus regarding the therapeutic approach of breast neuroendocrine carcinomas (NECs). As most NECs are hormone receptor positive and HER‐2 negative, we suggest that endocrine‐based strategies may play a leading role. Here, we report a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium. Primary neuroendocrine neoplasms of the breast constitute a rare entity. They are characterized by predominant neuroendocrine differentiation and are further divided into well‐differentiated neuroendocrine tumors and poorly differentiated (high‐grade) neuroendocrine carcinomas (NECs). Regarding their therapeutic approach, there are no standardized guidelines. Herein, we present the first case ever reported, concerning a female patient with de novo metastatic breast NEC who received hormonal therapy, a combination of a CDK4/6 inhibitor palbociclib with letrozole and triptorelin, as first‐line treatment with significant clinical and radiological response. As most NECs are estrogen receptor and/or progesterone receptor positive and HER‐2 negative, we suggest that hormonal therapy may play a leading role even in the first‐line setting. The present report provides a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium of breast NECs. [ABSTRACT FROM AUTHOR]

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Introduction: Aromatase inhibitor (AI)-induced musculoskeletal symptoms (AIMSS) can decrease health-related quality of life and lead to discontinuation of AI therapy for postmenopausal women with breast cancer (BC). Although central sensitization (CS) may contribute to AIMSS, the relevance of CS-related symptoms to AIMSS has not been fully clarified. This study aimed to investigate the relationship between AIMSS and CS-related symptoms in women with BC who received AI therapy. Methods: This cross-sectional study recruited women who underwent BC surgery before at least 1 year and were taking AI for at least 6 months. Participants were assessed for joint pain and CS-related symptoms using the central sensitization inventory (CSI). The severity of CS-related symptoms was classified into three groups, and the prevalence of AIMSS was calculated. Multiple logistic regression analysis was used to assess the relationship between AIMSS and factors of possible relevance to AIMSS, including CSI severity. Results: Of the 73 women who were included in this study, 31 (42.4%) were categorized into the AIMSS group and 42 (57.6%) into the non-AIMSS group. Participants with a history of chemotherapy and higher CSI score were significantly more likely to have AIMSS. Multiple logistic regression analysis showed that a history of chemotherapy (odds ratio = 4.21) and higher CSI severity (odds ratio = 13.43) had significantly associated with AIMSS. Conclusion: CS-related symptoms assessed using CSI may be strongly associated with AIMSS. Further longitudinal studies to investigate the causal relationship and effectiveness of CS-targeted interventions are needed to prevent and treat AIMSS effectively. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

It is generally assumed that all estrogen-receptor-positive (ER+) breast cancers proliferate in response to estrogen and, therefore, examples of the estrogen-induced regression of ER+ cancers are paradoxical. This review re-examines the estrogen regression paradox for the Luminal A subtype of ER+ breast cancers. The proliferative response to estrogen is shown to depend on the level of ER. Mechanistically, a window of opportunity study of pre-operative estradiol suggested that with higher levels of ER, estradiol could activate the DREAM-MMB (Dimerization partner, Retinoblastoma-like proteins, E2F4, and MuvB–MYB-MuvB) pathway to decrease proliferation. The response of breast epithelium and the incidence of breast cancers during hormonal variations that occur during the menstrual cycle and at the menopausal transition, respectively, suggest that a single hormone, either estrogen, progesterone or androgen, could activate the DREAM pathway, leading to reversible cell cycle arrest. Conversely, the presence of two hormones could switch the DREAM-MMB complex to a pro-proliferative pathway. Using publicly available data, we examine the gene expression changes after aromatase inhibitors and ICI 182,780 to provide support for the hypothesis. This review suggests that it might be possible to integrate all current hormonal therapies for Luminal A tumors within a single theoretical schema. [ABSTRACT FROM AUTHOR]

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment. [ABSTRACT FROM AUTHOR]

A class of drugs known as aromatase inhibitors can effectively inhibit aromatase, an enzyme that transforms androgens (male hormones) into estrogens (female hormones). These inhibitors are commonly used in medical treatments for hormone-sensitive conditions such as breast cancer in humans. In the context of fish, there has been some research on the use of aromatase inhibitors to alter the sexual development and secondary sexual characteristics of certain species. Aromatase inhibitors in fish may be used to manipulate sex ratios in aquaculture. In some fish species, the sexes of individuals are influenced by environmental variables, including temperature. By administering aromatase inhibitors, it is possible to suppress the production of estrogens and bias the sex ratio towards males. This can be desirable in certain aquaculture operations where males are preferred, such as for increased growth rates or reduced aggression. It is important to highlight that the use of hormone manipulation techniques in fish farming is subject to regulations and restrictions, as the potential environmental impacts and welfare considerations need to be carefully evaluated. The use of any pharmaceutical product in aquaculture requires rigorous testing and approval processes to ensure its safety and efficacy. This review discusses the multifaceted use of aromatase inhibitors in the manipulation of sex ratios in aquaculture, while emphasizing the imperative need for the systematic evaluation of environmental impacts and ethical considerations associated with this practice, and compliance with regulatory frameworks governing their implementation. [ABSTRACT FROM AUTHOR]

We assessed the real-world effectiveness of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as first-line treatments in postmenopausal patients with HR+/HER2− advanced breast cancer, focusing on younger (<45 years) and older (>78 years) populations not considered in clinical trials. We analyzed nationwide claims data from the Health Insurance Review and Assessment Service between November 2016 and February 2021. In this retrospective cohort study, patients using CDK4/6 inhibitors and aromatase inhibitors were selected and grouped by age as follows: 45–78 years (trial-enrolled), <45 years (younger), and >78 years (older). We estimated the median real-world progression-free survival (rwPFS) and overall survival (OS) using the Kaplan-Meier method. We conducted Cox regression analysis using a sub-distribution hazard model to evaluate risk factors (age, history of prior systemic treatment, presence of metastasis, comorbidity index, and type of provider) and estimated hazard ratios (HR). Among the 2,830 patients who received CDK4/6 inhibitors as first-line therapy, we identified 358 (12.65%) younger and 148 (5.23%) older underrepresented patients. The younger patient group (50.84%) had the highest rate of prior systemic therapy, followed by the trial-enrolled (25.39%) and older patient groups (8.11%). The median rwPFS was shorter in the older group (19.30 months) than those in the younger and the trial-enrolled age groups (30.33 and 34.53 months, respectively; p =.002). The HR of older age for death was 1.59 (95% confidence interval (CI) = 1.24–2.03). For rwPFS, the HR of prior systemic therapy was 1.19 (95% CI = 1.04–1.37). The younger age group, which was underrepresented in the trial, did not show a significant difference in risk compared with the enrolled age group. However, the older age group, which was also underrepresented in the trial, faces a risk of mortality but not progression. Patients who fall outside the specified age groups for the clinical trial can still expect the same level of effectiveness in terms of progression. [ABSTRACT FROM AUTHOR]

Purpose Male breast cancer (MBC) is a rare, but increasingly common disease, and lacks prospective studies. Collaborative efforts are needed to understand and address MBC, including its prognosis, in different countries. Methods We retrospectively reviewed the clinical, histopathological, and molecular-genetic characteristics, treatments, and survival outcomes of MBC diagnosed between 2007 and 2017 in the Czech Republic. Prognostic factors of overall survival (OS), recurrence-free interval (RFi), and breast cancer-specific mortality (BCSM) were analyzed and indirectly compared to international data. Results We analyzed 256 patients with MBC (median age 66 years), including 12% with de novo metastatic (M1). Of 201 non-metastatic (M0) patients, 6% were <40 years old, 29% had stage I, 55% were cN0, and 54% underwent genetic testing. Overall, 97% of tumors had estrogen receptor expression ≥10%, 61% had high Ki67 index, 40% were high-grade (G3), and 68% were luminal B-like (HER2-negative). Systemic therapies included endocrine therapy (90%) and chemotherapy (53%). Few (5%) patients discontinued adjuvant endocrine therapy for reasons other than disease relapse or death. Patients treated with aromatase inhibitors alone had significantly shorter RFi (P  < .001). OS, RFi, and BCSM were associated with disease stage, T stage, N stage, progesterone receptor expression, grade, and Ki67 index. Median OS reached 122 and 42 months in M0 and de novo M1 patients, respectively. Conclusion Due to the rarity of MBC, this study highlights important findings from real clinical practice. Although the number of patients with MBC with unfavorable features was higher in this Czech dataset than in international studies, the prognosis remains consistent with real-world evidence. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular biomarkers that also serve as predictive indicators. More than two thirds of breast tumors are classified as luminal with positive hormone receptors (HR), indicating that cancer cells proliferation is promoted by hormones. Endocrine therapies play a vital role in the effective treatment of breast cancer by manipulating the signaling of estrogen receptors (ER), leading to a reduction in cell proliferation and growth rate. Selective estrogen receptor modulators (SERMs), such as tamoxifen and toremifene, function by blocking estrogen's effects. Aromatase inhibitors (AI), including anastrozole, letrozole and exemestane, suppress estrogen production. On the other hand, selective estrogen receptor degraders (SERDs), like fulvestrant, act by blocking and damaging estrogen receptors. Tamoxifen and AI are widely used both in early- and advancedstage disease, while fulvestrant is used as a single agent or in combination with other agents like the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, ribociclib) or alpelisib for advanced-stage disease. Currently, SERDs are recognized as an effective therapeutic approach for the treatment of ER-positive breast cancer, showing proficiency in reducing and blocking ER signaling. This review aims to outline the ongoing development of novel oral SERDs from a practical therapeutic perspective, enhancing our understanding of the mechanisms of action underlying these compounds. [ABSTRACT FROM AUTHOR]

Simple Summary: Abemaciclib in combination with endocrine therapy is a standard first- or later-line of treatment for HR+/HER2− metastatic breast cancer (MBC). Real-world studies provide valuable addition to pivotal trials by including a heterogeneous patient population, particularly subgroups that are often underrepresented (e.g., elderly patients). This study retrospectively collected data on the efficacy and safety of abemaciclib in a real-world patient population. The safety and efficacy of the treatment were consistent with the pivotal studies, including in elderly patients. Comparable survival outcomes were observed between the first two lines of treatment. Additionally, metastatic disease survival was greatly prolonged, exceeding 5 years compared to historical data. The study provides further reassurance that dose reductions do not affect survival. The safety profile of abemaciclib was consistent with previous findings, and no new adverse events (AEs) were identified. Although abemaciclib was well tolerated in elderly patients, the careful monitoring and management of AEs is still warranted. (1) Background: Abemaciclib combined with endocrine therapy is a standard first- or later-line of treatment for HR+/HER2− metastatic breast cancer (MBC). The aim of this retrospective cohort study was to describe the outcomes of patients treated in a real-world setting, with particular focus on elderly patients. (2) Patients and methods: Patients treated with abemaciclib between November 2019 and February 2022 were included in the study. Data were collected from electronic medical records. The primary objective was to determine real-world progression-free survival (rwPFS), and secondary objectives included median overall survival (mOS) and safety. (3) Results: Analysis included 134 patients, with a median follow-up of 42 months. Median age was 62 years, with 29.9% aged 70+ years. A total of 51.5% of patients received abemaciclib in first-line, predominantly with aromatase inhibitor (68.1%). Median rwPFS was 21 in first-line and 20 months in the second-line, with no significant difference between treatment lines (HR 0.96; p = 0.88). Patients treated in the third- or later-line had a significantly shorter rwPFS, at 7 months (HR 1.48, p = 0.003). mOS was not reached in the first-line setting. For second- and third- or later-lines, mOS was 29 and 19 months, respectively. There was no significant difference in mOS between first- or second-line (HR 1.37, p = 0.36). In the 70+ group, median rwPFS was 15 months and mOS was 25 months with no significant difference compared to younger patients (rwPFS HR 1.1; p = 0.65; OS HR 1.4; p = 0.21). Most common adverse events (AEs) were diarrhoea (68.7%), anaemia (64.9%), and increased serum creatinine (63.4%). Grade 3/4 AEs were reported in 21.6% of patients. Dose reductions occurred in 30.6% of patients and were more frequent in patients 70+ (40%) compared to younger patients (28%); the difference was not significant (p = 0.22). At study cut-off, 64.9% of patients discontinued abemaciclib, primarily due to disease progression (73.5%). (4) Conclusions: Our study provides valuable insights into the effectiveness and safety of abemaciclib for the treatment of MBC. We observed comparable outcomes in terms of rwPFS and OS between the first two lines, suggesting consistent effectiveness across treatment lines. In addition, our findings suggest that older age (70+) does not significantly impact the effectiveness and tolerability of abemaciclib, although the careful monitoring and management of AEs are warranted. [ABSTRACT FROM AUTHOR]

Cancer-related pain is primarily treated with opioids which while effective can add significant patient burden due to side effects, associated stigma, and timely access. The purpose of this perspective discussion is to argue for a precision approach to pain in cancer based on a biopsychosocial and spiritual model which we argue can offer a higher quality of life while limiting opioid use. Pain in cancer represents a heterogenous process with multiple contributing and modulating factors. Specific characterization of pain as either nociceptive, neuropathic, nociplastic, or mixed can allow for targeted treatments. Additional assessment of biopsychosocial and spiritual issues can elucidate further points of targeted intervention which can lead to overall greater pain control. Precision Pain Management in Cancer Pain in cancer is complex and heterogeneous with multiple contributing etiologies. A comprehensive assessment addressing the biopsychosocial and spiritual aspects of pain may lead to better control. Utilizing multiple targeted treatment strategies may help to curb opioid use. [ABSTRACT FROM AUTHOR]

Simple Summary: Although women 70 years of age and older represent a large percentage of newly diagnosed breast cancer cases, older individuals are drastically underrepresented in clinical trials. Most women diagnosed with breast cancer at 70 years of age and older present with hormone receptor-positive (HR+) breast cancer. Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapy has become the standard of care for metastatic HR+ breast cancer. This study reports that metastatic breast cancer patients ≥70 years of age receiving CDK4/6 inhibitor-based treatment, particularly when combined with an aromatase inhibitor, experience prolonged progression-free survival but display no such prolongation in overall survival and report more frequent adverse effects to treatment. The reported findings can aid in the development of optimized treatments based on age and help older patients weigh treatment options. The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration. [ABSTRACT FROM AUTHOR]

Treatment with aromatase inhibitors (AIs) in patients with breast cancer can lead to dry eye disease (DED). The purpose of the study is to determine the prevalence and risk factors of DED in patients treated with AIs for breast cancer. Participants in this cross-sectional study were patients with breast cancer treated with AIs. Demographic and clinical data, including age, sex, type of cancer, stage, grade, duration of treatment and adjuvant chemotherapy and/or radiotherapy were collected. All patients underwent a detailed ophthalmic examination, as well as Tear Break up Time (TBUT) and Schirmer test, while Ocular Surface Disease Index (OSDI) questionnaires were administered. Based on the clinical findings, a diagnosis of DED was made, and prevalence was calculated. Univariate analysis of the association of different variables with DED was performed. A logistic regression analysis was done to identify risk factors for DED among study population. A total of 102 participants were included in the study. The mean age of patients was 62.4 ± 10.8 years. A total of 77 out of 102 patients (75.5%) had ductal, 16 (15.7%) lobular and 9 (8.8%) other types of breast cancer. A total of 83 patients (81.4%) received chemotherapy and 70 patients (68.6%) received radiotherapy. The mean duration of treatment was 24.4 ± 18.9 months. The prevalence of DED in the study sample was 69.6%. Patients who received radiotherapy (OR = 3.31, 95%CI = 1.30–7.82, p = 0.01) or were under treatment with AIs for more than 24 months (OR = 3.53, 95%CI = 1.47–9.21, p = 0.002) were found to have an increased risk of DED. There was a high prevalence of DED among the study population. Radiotherapy and duration of treatment with AIs were independently associated with DED. [ABSTRACT FROM AUTHOR]

Aromatase inhibitors (AIs) have shown great success as adjuvant therapy for post-menopausal women with hormone receptor–positive breast cancers. AI-induced arthralgia (AIA) is a frequent AI toxicity contributing to non-adherence and discontinuation. This review aims to understand current knowledge of AIA. The mean incidence of AIA was 39.1% and the mean discontinuation of AI therapy due to AIA was 9.3%. Most of the AIAs were non-inflammatory. A shorter time since the last menstrual period and pre-existing joint pain were risk factors. Vitamin D3 supplementation may be a preventative measure and treatment with duloxetine, acupuncture and/or exercise is supported by large randomized controlled trials. There was consistent improvement in AIAs with switching to an alternate AI, and this could additionally allow continuation of cancer treatment with AI. Further research is needed to identify predictive biomarkers, better characterize AIA subcategories and study more reliable therapeutic options. [ABSTRACT FROM AUTHOR]