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BackgroundThe first phase of the GAIL study (“Girls treated with an Aromatase Inhibitor and Leuprorelin,” ISRCTN11469487) has shown that the combination of anastrozole and leuprorelin for 24 months is safe and effective in improving the predicted adult height (PAH) in girls with early puberty and compromised growth prediction by +1.21 standard deviation score (SDS; +7.51 cm) compared to inhibition of puberty alone, +0.31 SDS (+1.92 cm).Objectives and hypothesesIn the second phase of the GAIL study, we assessed the adult height (AH)/near-adult height (NAH) at the end of the first phase and, in addition, the efficacy of anastrozole monotherapy thereafter in further improving NAH.MethodsWe measured the AH (age 16.5 years)/NAH [bone age (BA), 15 years] of the 40 girls included, divided into two matched groups: group A (20 girls on anastrozole + leuprorelin) and group B (20 girls on leuprorelin alone). Group A was further randomized into two subgroups: A1 and A2. Group A1 (n = 10), after completion of the combined therapy, received anastrozole 1 mg/day as monotherapy until BA 14 years, with a 6-month follow-up. Group A2 (n = 10) and group B (n = 20), who received only the combined treatment and leuprorelin alone, respectively, were recalled for evaluation of AH/NAH.ResultsAH or NAH exceeded the PAH at the completion of the 2-year initial phase of the GAIL study in all groups, but the results were statistically significant only in group A1: NAH–PAH group A1, +3.85 cm (+0.62 SDS, p = 0.01); group A2, +1.6 cm (+0.26 SDS, p = 0.26); and group B, +1.7 cm (+0.3 SDS, p = 0.08). The gain in group A1 was significantly greater than that in group A2 (p = 0.04) and in group B (p = 0.03). Anastrozole was determined to be safe even as monotherapy in Group A1.ConclusionsIn early-maturing girls with compromised growth potential, the combined treatment with leuprorelin and anastrozole for 2 years or until the age of 11 years resulted in a total gain in height of +9.7 cm when continuing anastrozole monotherapy until the attainment of NAH, as opposed to +7.4 cm if they do not continue with the anastrozole monotherapy and +3.6 cm when treated with leuprorelin alone. Thus, the combined intervention ends at the shortest distance from the target height if continued with anastrozole monotherapy until BA 14 years.

Breast cancer with isolated orbital metastasis is a rare clinical entity. We hereby present a rare case report of 35 year old premenopausal lady with known case of carcinoma breast right side (operated for right modified radical mastectomy in year 2017 with final histopathology of pT2N2M0, hormone receptor-positive and Her2-negative disease). She completed adjuvant 8 cycles of standard dose chemotherapy with 4 cycles of Cyclophosphamide, Adriamycin followed by 4 cycles of Paclitaxel followed by local Radiation therapy. She was initiated Tab. Tamoxifen 20 mg once daily and was continued same for 4 years when in July 2021, she complained of sudden decreased visual acuity and diplopia of right eye lasting from last 1 month. Ophthalmological examination confirmed the findings with decreased visual acuity of 6/36 of right eye while visual acuity of left eye was normal. CT scan of orbits revealed 28 × 18mm heterogeneous enhancing soft tissue mass in right orbital compartment, extrabulbar, occupying postero-superior quadrant inseparable from lateral rectus muscle with optic nerve effacement. PET-CT scan was performed which revealed no metastasis elsewhere in the body. She was offered surgical oophorectomy followed by switch to another hormonal therapy of aromatase inhibitors. She showed complete response to treatment and is now disease from last 2 years. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) occupies a leading position among all malignant neoplasms in women worldwide and is the 4th deadliest. Most cases are diagnosed in stages I–III. Among the molecular biological variants, luminal HER2 negative (HER2-) prevails, accounting for 70–75%. Currently, therapies combining surgery with chemotherapy and, more rarely, radiation therapy, followed by adjuvant hormone therapy for up to 10 years, are a standard of care in BC. The goal of these regimens is the prevention of early recurrence in patients in the high-risk group with a primary hormone-resistant tumor. However, at the end of treatment, it occurs in 27–57% of patients with stage II–III breast cancer. For its prevention in early HR-positive (HR+) HER2- BC, an innovative class of drugs, cyclin-dependent kinase 4/6 inhibitors, is used combined with hormone therapy (aromatase inhibitors, anti-estrogens, gonadotropin-releasing hormone agonists), which is the subject of a randomized phase III NATALEE study evaluating the efficacy and safety of ribociclib in combination with endocrine therapy in early non-metastatic BC. The study enrolled patients with stage II–III breast cancer, including those with N0. Patients of the study group received ribociclib at a dose of 400 mg/day for 21 days in combination with aromatase inhibitors, and in the control group, only aromatase inhibitors. The median follow-up was 34 months. Three-year survival without invasive disease was 90.7% in the ribociclib group and 87.6% in controls. The risk of distant metastasis and invasive diseases was reduced by 25.1% in the ribociclib group. Therefore, ribociclib tended to improve overall survival. The initial dose of 400 mg/day reduced the incidence of adverse events; the most common were neutropenia (62.5%), arthralgia (37.3%) and hepatic toxicity (26.4%). The most common reasons for discontinuing ribociclib were hepatic toxicity (8.9%) and arthralgia (1.3%). The results demonstrate a statistical and clinical superiority of ribociclib in combination with hormone therapy in the treatment of early HR+ HER2- breast cancer with a high risk of recurrence.

Aim: Cholesterol is an essential component of cell membranes and serves as a precursor for several bioactive molecules, including steroid hormones and isoprenoids. Generally supplied by the bloodstream, the de novo cholesterol biosynthesis is activated in response to an increased cell requirement due to normal tissue remodeling or tumor proliferation. In estrogen receptor (ER)-positive breast cancers, cholesterol biosynthesis may promote and sustain tumor growth and concur with the failure of the treatment with aromatase inhibitors. Methods: In this study, the comparison of gene compared the expression involved in cholesterol biosynthesis was conducted in ER-positive tumors that were responsive and nonresponsive to letrozole; besides, an exploration of their association with genes implicated in estrogen production, the Hippo pathway, and cell cycle control was performed. Results: In responsive tumors, letrozole significantly decreased the expression of five genes [acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), farnesyl diphosphate synthase (FDPS), and squalene epoxidase (SQLE)] crucial for the biosynthetic process. Conversely, in nonresponsive tumors, these genes were unaffected by letrozole but associated with several genes involved in estrogens production [cytochrome P450 family 19 subfamily A member 1 (CYP19A1), hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2), and sulfotransferase family 1A member 1 (SULT1A1)], cell cycle [control cyclin dependent kinase 4 (CDK4) and CDK6], and Hippo pathway [Yes1 associated transcriptional regulator (YAP1) and baculoviral inhibitor of apoptosis (IAP) repeat containing 5 (BIRC5)]. Conclusions: The findings corroborated the notion that the dysregulation of the mevalonate pathway may contribute to the resistance to letrozole and supported the use of statins to contrast this metabolic dysfunction.

Abstract Background This retrospective study explored the effect on adult height of a combination of recombinant human growth hormone (rhGH) and aromatase inhibitors (AIs), or rhGH and a gonadotropin-releasing hormone analog (GnRHa), and compared their effects with rhGH alone in males at advanced bone age with idiopathic short stature (ISS). Methods In this retrospective study, rhGH or rhGH combined with GnRHa or rhGH combined with AI therapy was given to males with advanced bone age (13–15 years) and diagnosed with ISS. The patients were followed to assess their adult height. Results (1) A total of 68 patients were reviewed; 22 males were treated with rhGH for 24.9 ± 4.47 months, 22 males were treated with GnRHa + rhGH for 34.1 ± 3.36 months, and 24 males were treated with AI + RHGH for 22.7 ± 2.49 months. (2) Before treatment, the HtSDS-CA for the three groups were -1.04 ± 0.95, -1.23 ± 1.06, and -0.85 ± 0.98, respectively, and the HtSDS-BA were -2.14 ± 0.29, -2.14 ± 0.21, and-2.26 ± 0.31, respectively. The target heights for each group were 169.7 ± 4.0 cm, 169.7 ± 3.9 cm, and 169.1 ± 3.9 cm, respectively. The predicted adult heights were 161.7 ± 3.35 cm, 162.3 ± 1.75 cm, and 161.6 ± 2.89 cm, respectively. (3) After treatment, the HtSDS-CA for the rhGH group increased by 1.30 ± 0.58, and the HtSDS-BA increased by 2.00 ± 0.27. For the GnRHa + rhGH group, the HtSDS-CA and HtSDS-BA increased by1.42 ± 0.73and 2.74 ± 0.28, respectively. The AI + RHGH group increased by1.39 ± 0.64 and 2.76 ± 0.31, respectively. (4) There was no significant difference between the adult height (170.9 ± 0.7 cm) and target height for the rhGH group (P > 0.05), but the adult heights for the GnRHa + rhGH and AI + RHGH groups (173.2 ± 1.5 cm and 173.5 ± 1.0 cm, respectively, P > 0.05) were higher than the target height (P

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.

Introduction: Hormonal therapy (HT) blocks the hormone-mediated growth signal dramatically reducing estrogenic levels with aromatase inhibitors (AIs) becoming a crucial component of the treatment mainstay in patients with early breast cancer (BC). Postmenopausal BC patients receiving HT present with a significant risk of secondary osteoporosis with AIs further reducing estrogen levels and ultimately leading to an accelerated rate of bone resorption and thus decreased bone mineral density (BMD). This was an observational retrospective clinical study that consecutively enrolled early BC patients with osteopenia to compare the impact of alendronate versus denosumab on secondary osteoporosis prevention and pain control. Methods: We identified two groups of patients treated with denosumab 60 mg by subcutaneous injection once every six months or alendronate 70 mg orally once a week. All the patients underwent a baseline physiatric evaluation (T0) and underwent a follow-up visit after 18 months (T1) together with femoral and vertebral Dual-Energy X-ray Absorptiometry (DEXA) exam evaluating T-Score marks. From September 2015 to December 2019 a total of 50 early (stage I-III) BC patients were considered eligible and consecutively enrolled in our study if they met pre-specified inclusion criteria. Results: In the entire observed population, the addition of treatment with alendronate or denosumab led to a significant T-score improvement at the lumbar spine level (-1.92 vs -1.52, p=0.03), with a comparable contribution from alendronate (-1.60 vs -1.45, p=0.07) and denosumab (-2.26 vs -1.58, p=0.07). Regarding the femoral region, neither alendronate (-0.98 vs -1.07, p=0.23) nor denosumab (-1.39 vs -1.34, p=0.81) were able to produce any statistically relevant effect. However, concerning pain control, BMAs had a significant impact on reducing NRS scoresin the general population (T1 3.94 vs. baseline 4.32, p=0.007), with a likelyspecific contribution from alendronate (T1 3.52 vs. baseline 3.88, p=0.004) compared to denosumab (T1 4.36 vs baseline 4.76, p=0.12), without any differences in analgesic therapy assumption over time (p=0.93). Discussion: Both alendronate and denosumab significantly contributed to preventing secondary osteoporosis in early BC patients with low BMD undergoing AIs, mostly at the lumbar spine level. Moreover, alendronate seemed to significantly impact pain control in such patients further supporting alendronate as a costeffective option in this frail setting, although BMAs particularities should be carefully considered on an individual basis according to specific clinical contexts. [ABSTRACT FROM AUTHOR]

Background: This retrospective study explored the effect on adult height of a combination of recombinant human growth hormone (rhGH) and aromatase inhibitors (AIs), or rhGH and a gonadotropin-releasing hormone analog (GnRHa), and compared their effects with rhGH alone in males at advanced bone age with idiopathic short stature (ISS). Methods: In this retrospective study, rhGH or rhGH combined with GnRHa or rhGH combined with AI therapy was given to males with advanced bone age (13–15 years) and diagnosed with ISS. The patients were followed to assess their adult height. Results: (1) A total of 68 patients were reviewed; 22 males were treated with rhGH for 24.9 ± 4.47 months, 22 males were treated with GnRHa + rhGH for 34.1 ± 3.36 months, and 24 males were treated with AI + RHGH for 22.7 ± 2.49 months. (2) Before treatment, the HtSDS-CA for the three groups were -1.04 ± 0.95, -1.23 ± 1.06, and -0.85 ± 0.98, respectively, and the HtSDS-BA were -2.14 ± 0.29, -2.14 ± 0.21, and-2.26 ± 0.31, respectively. The target heights for each group were 169.7 ± 4.0 cm, 169.7 ± 3.9 cm, and 169.1 ± 3.9 cm, respectively. The predicted adult heights were 161.7 ± 3.35 cm, 162.3 ± 1.75 cm, and 161.6 ± 2.89 cm, respectively. (3) After treatment, the HtSDS-CA for the rhGH group increased by 1.30 ± 0.58, and the HtSDS-BA increased by 2.00 ± 0.27. For the GnRHa + rhGH group, the HtSDS-CA and HtSDS-BA increased by1.42 ± 0.73and 2.74 ± 0.28, respectively. The AI + RHGH group increased by1.39 ± 0.64 and 2.76 ± 0.31, respectively. (4) There was no significant difference between the adult height (170.9 ± 0.7 cm) and target height for the rhGH group (P > 0.05), but the adult heights for the GnRHa + rhGH and AI + RHGH groups (173.2 ± 1.5 cm and 173.5 ± 1.0 cm, respectively, P > 0.05) were higher than the target height (P < 0.05). (5) Compared with the predicted adult height, the adult heights for the three groups improved significantly (P < 0.05). (6) No severe adverse reactions during the treatment occurred in any of the children. However, the total incidence of side effects in the three groups was significant (χ2 = 20.433, P = 0.00). Conclusion: Different therapeutic approaches have been investigated to improve the final adult height of males at advanced bone ages with ISS, and the optimal strategy remains controversial. In children at advanced bone ages with ISS, clinicians should carefully consider the advantages and disadvantages prior to treatment. [ABSTRACT FROM AUTHOR]

Objective: Palbociclib, a highly selective reversible CDK4-6 kinase inhibitor, is indicated in combination with an aromatase inhibitor or in combination with fulvestrant in women who had received prior endocrine treatment. Studies have demonstrated the efficacy of palbociclib in combination with fulvestrant in increasing progression-free survival in patients who relapsed or progressed on previous endocrine therapy, or in combination with aromatase inhibitor in patients who had not received previous treatments. We analysed the prescribing patterns of palbociclib in real practice correlating it with the evidence of treatment-related toxicity management and to time-to-treatment discontinuation and treatment adherence. Methods: For the observational, retrospective study, data were collected from five Italian hospital centres that prescribed palbociclib between April 2017 and April 2020. Each centre provided data derived from an administrative database of adult patients treated with palbociclib for the two therapeutic indications. Treatment adherence was calculated using the proportion of days covered method while time-to-treatment discontinuation was defined as the difference between the first and last date treatment was administered plus the days ideally covered by the last date treatment was given. Results: There were 375 patients enrolled during the study period, of whom 159 were treated with palbociclib and aromatase inhibitor and 216 were treated with palbociclib and fulvestrant. The time-to-treatment discontinuation was 8.9 months in the case of P + f (95% CI: 7.1−12.7) and 13.7 months in the case of P + ia (95% CI: 8.9−17.5). In both cohorts, treatments that received at least one dose reduction had a statistically higher time-to-treatment discontinuation than those without dose reduction (17.7 months vs. 9.2 and 16.6 vs. 7.4). The mean adherence in our study was 0.9 and remained high in treatments with one dose reduction (0.83) and this with two dose reductions (0.87). Conclusion: Based on these findings, it appears that the management of toxicities through reducing doses, as required by the Summary of Product Characteristics, results in a better outcome in terms of therapy duration, and therefore time to failure due to progression or toxicity. [ABSTRACT FROM AUTHOR]

Shared decision-making involves patients engaging with their physicians to make informed decisions regarding treatment selection, a process that empowers patients and ensures that treatment decisions reflect their individual values and preferences. However, shared decision-making can be challenging to implement for various reasons, including time, staffing, or resource limitations at community practices and differences in patients' cultural backgrounds or health literacy. In this podcast, we discuss how to ensure that individual patients' needs and concerns are addressed, including an overview of different approaches for initial consultations, strategies for tailoring conversations based on a patient's background or health literacy, and trustworthy resources that can help improve patients' understanding. As an illustrative example, we focus on how to implement shared decision-making to address the needs of a patient with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer who is eligible for combination therapy with a cyclin-dependent kinase 4/6 inhibitor plus an aromatase inhibitor. Overall, this podcast illustrates how shared decision-making is an achievable goal, even in small or underresourced practices, and provides an instructive guide on how to facilitate shared decision-making for patients with HR+/HER2− metastatic breast cancer. BckE49qAyYLe9j8jEQBXts Podcast Discussion (MP4 29880 KB) Infographic: [ABSTRACT FROM AUTHOR]

Aromatase enzyme plays a fundamental role in the development of estrogen receptors, and due to this functionality, the enzyme has gained significant attention as a therapeutic for reproductive disorders and cancer diseases. The currently employed aromatase inhibitors have severe side effects whereas our novel aromatase inhibitor is more selective and less toxic, therefore has greater potential to be developed as a drug. The research framework of this study is to identify a potent inhibitor for the aromatase target by profiling molecular descriptors of the ligand and to find a functional pocket in the target by docking and MD simulations. For assessing cellular and metabolic activities as indicators of cell viability and cytotoxicity, in-vitro studies were performed by using the colorimetric MTT assay. Aromatase activities were determined by a fluorometric method. Cell morphology was assessed by phase-contrast light microscopy. Flow cytometry and Annexin V-FITC/PI staining assay determined cell cycle distribution and apoptosis. This study reports that CHEMBL708 (Ziprasidone) is the most promising compound that showed excellent aromatase inhibitory activity. By using better drug design methods and experimental studies, our study identified a novel compound that could be effective as a high-potential drug candidate against aromatase enzyme. We conclude that the compound ziprasidone effectively blocks the cell cycle at the G1-S phase and induces cancer cell death. Further, in-vivo studies are vital for developing ziprasidone as an anticancer agent. Lastly, our research outcomes based on the results of the in-silico experiments may pave the way for identifying effective drug candidates for therapeutic use in breast cancer. [ABSTRACT FROM AUTHOR]

The objective of this study was to reveal the growth, colouration and gonado-physiological changes due to the exogenous aromatase inhibitor (AIs) in an ornamental fish. 17α-methyltestosterone (MT) and letrozole (LET) were used as potential AIs. The AI were supplemented with a gel-based feed (LET: 50, 100, 150 and MT: 12.5, 25, 37.5 mg/kg feed) in Rosy barb, Pethia conchonius fry. The fishes were reared in a 45-L glass tank using AI treated gel-based feed for 3 months. Growth in AI-based diets was reduced but the reduction was minimal compared to the control. At 25 mg/kg feed of 17 MT, the highest male proportion (84.72% 6.05%) was recorded, which was significantly higher (P≤0.05) than other groups. L*, a*, and b* values showed that 17α-MT-fed groups had brighter coloration (P≤0.05). Histological sections showed that LET-17α-MT suppressed ovarian development, causing atretic oocytes. Testicular development was unaffected. 25 mg/kg-treated feed increased SOD, CAT, GST, and GPX. The AI (MT) at 25 mg/kg gel-based feed could therefore be utilised for musculinization without impacting growth, colour, and antioxidant activity of rosy barb, which serves the entire male population in the ornamental fish sector. [ABSTRACT FROM AUTHOR]

Simple Summary: Palbociclib combined with an aromatase inhibitor (AI) has been shown to be effective in clinical trials for people with HR+/HER2− breast cancer that has spread to other areas of the body, such as the lungs or liver. Evidence of palbociclib effectiveness in routine clinical practice can provide complementary support for clinical trial findings. This study used electronic health records of people with breast cancer that had spread to their lungs and/or liver to determine how well palbociclib plus an AI worked compared to an AI alone. The study showed that palbociclib plus an AI compared with an AI alone was associated with a 38% or 27% reduction in the risk of death for patients with breast cancer that had spread to the lungs or liver, respectively. These findings support the use of palbociclib plus an AI for people whose breast cancer has spread to their lungs or liver. A cyclin-dependent kinase 4/6 inhibitor combined with endocrine therapy is the standard of care for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2−) metastatic breast cancer (mBC), but real-world effectiveness data for patients with lung or liver metastases are limited. This retrospective study included data from the US Flatiron Health database of patients with HR+/HER2− mBC and lung or liver metastases treated with first-line palbociclib (PAL) plus an aromatase inhibitor (AI) or an AI alone in routine clinical practice. Overall survival (OS) and real-world progression-free survival (rwPFS) were assessed. A total of 891 patients were included (622 with lung metastasis, 376 with liver metastasis, and 107 with both lung and liver metastasis). After stabilized inverse probability of treatment weighting to balance patient characteristics, PAL + AI versus AI alone was associated with significantly prolonged OS (HR = 0.62; p < 0.001) and rwPFS (HR = 0.55; p < 0.001) in patients with lung metastases and numerically longer OS (HR = 0.73; p = 0.056) and significantly longer rwPFS (HR = 0.57, p < 0.001) for those with liver metastases. Overall, PAL + AI versus AI alone was associated with prolonged OS and rwPFS in routine clinical practice, supporting the use of first-line PAL + AI for patients with HR+/HER2− mBC with lung and/or liver metastases. [ABSTRACT FROM AUTHOR]

Simple Summary: The cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors palbociclib, ribociclib and abemaciclib have transformed the lives of patients with ER+/HER2− metastatic breast cancer (MBC). Clinical trials have shown that all three CDK4/6 inhibitors improve progression-free survival (PFS), but only ribociclib and abemaciclib improve overall survival (OS). The data have generated debate in the oncology community as to which CDK4/6 inhibitor to use in routine clinical practice. In this context, real-world data in a heterogeneous population of advanced breast cancer patients can inform clinical decision-making. Here, in a cohort of 227 patients, we show that palbociclib and ribociclib have similar PFS and OS benefits in the real world. Our data should reassure oncologists that both palbociclib and ribociclib remain effective treatment options for patients. The CDK4/6 inhibitors significantly increase progression-free survival (PFS) in ER+/HER2− advanced breast cancer patients. In clinical trials, overall survival (OS) improvement has been demonstrated for ribociclib and abemaciclib but not for palbociclib. We undertook a real-world evaluation of PFS and OS in 227 post-menopausal patients who received first-line CDK4/6 inhibitors. There is no significant difference in median PFS (27.5 months vs. 25.7 months, p = 0.3) or median OS (49.5 months vs. 50.2 months, p = 0.67) in patients who received either palbociclib or ribociclib, respectively. De novo disease is significantly associated with prolonged median PFS and median OS compared with recurrence disease (47.1 months vs. 20.3 months (p = 0.0002) and 77.4 months vs. 37.3 months (p = 0.0003), respectively). PR– tumours have significantly reduced median PFS and OS compared with PR+ disease (19.2 months vs. 38 months (p = 0.003) and 34.3 months vs. 62.6 months (p = 0.02), respectively). In the very elderly (>80 years), median PFS and OS are significantly shorter compared with patients who are 65 years or below (14.5 months vs. 30.2 months (p = 0.01), and 77.4 months vs. 29.6 months (p = 0.009), respectively) in the palbociclib group. Our data suggest that the benefit in the very elderly is limited, and PR+/de novo disease obtains the maximum survival benefit. [ABSTRACT FROM AUTHOR]

Simple Summary: Endocrine therapy (ET) remains the mainstay of treatment for Hormone Receptor-positive breast cancer, both in the early and advanced settings. The acquisition of mutations in the ESR1 gene encoding the estrogen receptor represents one of the main resistance mechanisms to ET. A conventional tumor tissue biopsy can be used to detect ESR1 mutations; however, these mutations are less likely to present on initial tissue biopsy, and such an invasive approach is hardly repeatable over time for longitudinal disease monitoring. The research of ESR1 mutations in liquid biopsies based on the analysis of circulating cell-free DNA in plasma is of increasing interest and has been recently recommended to guide therapy in patients with estrogen receptor-positive breast cancers at progression under ET. This comprehensive review reports the most recent advances and recommendations in this field and compares the different techniques available for the analysis of the ESR1 gene in liquid biopsy. The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment of HR+ BCs and include selective ER modulators, aromatase inhibitors, and selective ER downregulators. ET is the mainstay of adjuvant treatment in the early setting and the backbone of the first-line treatment in an advanced setting; however, the emergence of acquired resistance can lead to cancer recurrence or progression. The mechanisms of ET resistance are often related to the occurrence of mutations in the ESR1 gene, which encodes the ER-alpha protein. As ESR1 mutations are hardly detectable at diagnosis but are present in 30% to 40% of advanced BC (ABC) after treatment, the timeline of testing is crucial. To manage this resistance, ESR1 testing has recently been recommended; in ER+ HER2− ABC and circulating cell-free DNA, so-called liquid biopsy appears to be the most convenient way to detect the emergence of ESR1 mutations. Technically, several options exist, including Next Generation Sequencing and ultra-sensitive PCR-based techniques. In this context, personalization of ET through the surveillance of ESR1 mutations in the plasma of HR+ BC patients throughout the disease course represents an innovative way to improve the standard of care. [ABSTRACT FROM AUTHOR]

The present work describes an efficient and convenient synthesis of a library of novel 1, 2-bis- (tetrasubstituted-benzylidene) hydrazine an analogue (3-7) 1,2-bis (3-methoxy-2-hydroxybenzlidene) hydrazine (3) and 1,2-bis (6-bromo-3-methoxy 2-hydroxybenzylidene) hydrazine (4), were obtained via opening of ester coumarin derivatives (1 and 2) with hydrazine hydrate under reflux. Diazotization of compound 4 with aryldiazonium chloride led to the formation of 1,2-bis (6-bromo-5-arylazo-3-methoxy-2-hydroxybenzylidene) hydrazine (6a,b). Acetylation of compounds 4 and 6a with acetic anhydride afforded the corresponding 1,2-bis (6-bromo-5-substituted-3-methoxy-2-acetoxy benzylidene) hydrazines (5 and 7). The cytotoxicity screening of some synthesized 1,2-bis (tetra substituted benzylidene) hydrazines (4-7) against breast cancer cell lines (MCF-7), and it was found several active compounds. Meanwhile compound 5 exhibited cytotoxic activity compared to reference drug. The DNA flow cytometry on MCF-7 cells of compound 5 was determined, it was found to cause G2/M phase arrest and induce apoptosis in all G1/M phases. In addition, compound 5 has been tested in other trials against aromatase inhibitors and tyrosinase inhibitors. [ABSTRACT FROM AUTHOR]

Pain is a problem affecting women with breast cancer (HR+BrCa) receiving aromatase inhibitor (AI) therapy. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in DNA repair and oxidative stress genes and perceived worst pain after 6 months of AI therapy. We explored 39 SNPs in genes involved in DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) and oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) in women with HR+BrCa receiving adjuvant therapy (AI ± chemotherapy; n = 138). Pain was assessed via the Brief Pain Inventory. Hurdle regression was used to evaluate the relationship between each associated allele and (1) the probability of pain and (2) the severity of worst pain. ERCC2rs50872 and ERCC5rs11069498 were associated with the probability of pain and had a significant genetic risk score (GRS) model (p = 0.003). ERCC2rs50872, ERCC5rs11069498, ERCC5rs4771436, ERCC5rs4150360, PARP1rs3219058, and SEPP1rs230819 were associated with the severity of worst pain, with a significant GRS model (conditional mean estimate = 0.45; 95% CI = 0.29, 0.60; p < 0.001). These results suggest DNA repair and oxidative stress pathways may play a role in the probability of pain and the severity of worst pain. As healthcare delivery moves towards the model of precision healthcare, nurses may, in the future, be able to use these results to tailor patient care based on GRS. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer and its treatments may increase the risk of type 2 diabetes (T2D). We conducted a systematic review and meta-analysis to investigate the association between breast cancer and the incidence of T2D overall, and according to breast cancer treatments. Methods: We searched PubMed, Embase and references of relevant papers for studies on breast cancer, breast cancer treatment, and subsequent T2D risk. Using random-effects models, we calculated effect estimates and associated 95% confidence intervals of the association between breast cancer, adjuvant breast cancer treatments (i.e., endocrine therapy (tamoxifen, aromatase inhibitors, and combined) and chemotherapy), and subsequent T2D. We used funnel plots to assess publication bias. Results: Among 15 eligible studies, 10 reported on T2D risk after breast cancer, chemotherapy, or endocrine therapy; five studies investigated more than one association. Compared with patients without breast cancer, those with breast cancer and those who received any endocrine therapy had elevated risk of incident T2D (EE = 1.23, 95% CI = 1.13–1.33 and EE = 1.23, 95% CI = 1.16–1.32, respectively). Among breast cancer patients only, the risk of T2D was higher for those who received tamoxifen compared with those who did not receive tamoxifen (EE = 1.28, 95% CI = 1.18–1.38). Due to few studies, analyses investigating T2D risk after treatment with aromatase inhibitors or chemotherapy were inconclusive. Conclusion: Our findings suggest an elevated risk of T2D in breast cancer survivors, particularly after tamoxifen therapy. Further research is needed to determine the impact of aromatase inhibitors, and chemotherapy on the incidence of T2D after breast cancer. [ABSTRACT FROM AUTHOR]

Background: Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated how inhibiting the biosynthesis of estrogens with letrozole (an aromatase inhibitor) could affect the observed sex differences in ketamine's antidepressant-like-response. Methods: We performed several consecutive studies in adult Sprague–Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference). Results: The main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogens production with letrozole induced on itself an antidepressant-like response in female rats, while also increased ketamine's response in male rats (i.e., quicker response observed after only a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs. Conclusions: The present results demonstrated a sex-specific role for aromatase inhibition with letrozole in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole itself presented as a potential antidepressant for females with persistent effects over time. Clearly, the production of estrogens is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies. Highlights: There are clear sex differences in the antidepressant-like effects of ketamine. Ketamine showed efficacy in adult male rats while rendered ineffective in females. Aromatase inhibition with letrozole improved the effects observed in male rats. Aromatase inhibition with letrozole induced an antidepressant-like effect in females. The antidepressant-like effects of ketamine or letrozole persisted up to 2 months. Plain language summary: Ketamine is a novel fast-acting antidepressant recently approved for treatment-resistant depression. Since preclinical studies showed sex differences in its efficacy, probably driven by sex hormones (estrogens and testosterone), we evaluated the antidepressant-like effects of ketamine in male and female rats when the biosynthesis of estrogens was inhibited. To do so, we utilized letrozole, an inhibitor of the aromatase enzyme responsible for the conversion of testosterone into estrogens. The results showed, in line with the prior literature, sex-differences in the antidepressant-like response of ketamine; with efficacy in male rats and a lack of response for females. Aromatase inhibition with letrozole induced a faster response for ketamine in male rats, while did not change the lack of response for females. However, aromatase inhibition on itself was capable of inducing an antidepressant-like response in female rats. Interestingly, both ketamine's and letrozole's antidepressant-like effects in male and female rats respectively showed long-term beneficial effects, up to 65 days post-treatment. [ABSTRACT FROM AUTHOR]

A novel series of 1,2,3-triazole/1,2,4-triazole hybrids 5a, 5b, and 6a–i was designed and synthesized as antiproliferative agents targeting aromatase enzymes. The antiproliferative activity of the new hybrids against four cancer cells was studied using Erlotinib as a control. Compounds 6a and 6b demonstrated the highest antiproliferative activity among these hybrids, with GI50 values of 40 nM and 35 nM, respectively. Compound 6b was the most potent derivative, with a GI50 of 35 nM, comparable to Erlotinib's GI50 of 33 nM. Compound 6b inhibited all cancer cell lines with comparable efficacy to Erlotinib. Compounds 5a, 5b, and 6a–i were tested for inhibitory action against aromatase as a potential target for their antiproliferative activity. Results revealed that compounds 6a and 6b were the most potent aromatase inhibitors, with IC50 values of 0.12 ± 0.01 µM and 0.09 ± 0.01 µM, respectively, being more potent than the reference Ketoconazole (IC50 = 2.6 ± 0.20 µM) but less potent than Letrozole (IC50 = 0.002 ± 0.0002). These findings indicated that compounds 6a and 6b had significant aromatase inhibitory action and are potential antiproliferative candidates. The findings were further linked to molecular docking investigations, which gave models of strong interactions with the aromatase domain for inhibitors with high binding scores. [ABSTRACT FROM AUTHOR]

Background: Elderly patients are generally underrepresented in oncology clinical trials; therefore, real-world data are needed to inform clinical management of elderly patients with hormone receptor--positive/human epidermal growth factor receptor 2--negative (HR+/HER2-) metastatic breast cancer (mBC). This subanalysis of the P-REALITY X study (NCT05361655) evaluated palbociclib treatment patterns and comparative effectiveness of palbociclib plus an aromatase inhibitor (AI) versus an AI alone among patients with HR+/HER2-mBC aged ≥ 75 years treated in routine clinical practice in the United States. Methods: This retrospective observational cohort study used electronic health records from the Flatiron Health Analytic Database. Palbociclib treatment patterns, overall survival (OS), real-world progression-free survival (rwPFS), and time to chemotherapy (TTC) were evaluated. Three methods were used for comparative analyses: (1) an unadjusted analysis, (2) stabilized inverse probability treatment weighting (sIPTW; primary analysis), and (3) propensity score matching (PSM; sensitivity analysis). Results: A total of 961 patients aged ≥ 75 years with HR+/HER2- mBC were identified who started palbociclib plus an AI (n = 313) or an AI alone (n = 648) as first-line (1L) therapy between February 2015 and March 2020 (data cut-off: September 30, 2020). Among patients in the palbociclib plus an AI group with a documented palbociclib starting dose (n = 306), approximately 75% started palbociclib at 125 mg/day, and approximately 40% experienced dose adjustment. After sIPTW, patients treated with palbociclib plus an AI versus an AI alone had significantly improved OS (median of 43.0 vs. 32.4 months; hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.51--0.84]; P = 0.0007), rwPFS (median of 20.0 vs. 15.0 months; HR, 0.72 (0.59--0.89); P = 0.0021), and TTC (median of 40.2 vs. 27.4 months; HR, 0.69 [0.55--0.87]; P = 0.0014). These significant improvements in OS, rwPFS, and TTC remained consistent in the unadjusted analysis and after PSM. Conclusion: This real-world comparative analysis demonstrated that 1L palbociclib plus an AI is associated with improved effectiveness compared with an AI alone among patients with HR+/HER2 -mBC aged ≥ 75 years. These findings support palbociclib plus an AI as a standard-of-care 1L treatment for elderly patients with HR+/HER2- mBC. [ABSTRACT FROM AUTHOR]

Background: Oral complications from cancer treatments are among the adverse effects breast cancer survivors can face. Yet such complications are often overlooked in cancer survivorship care. Many breast cancer survivors are receiving adjuvant endocrine therapy, but there is limited understanding of potential oral complications from this therapy. Purpose: This study aimed to compare aspects of oral health in female breast cancer survivors who were taking adjuvant endocrine therapy with those of survivors not taking such therapy. Methods: National Health and Nutrition Examination Survey data collected from January 2009 through March 2020 were used for the analysis. Female adults ages 20 years and older who had been diagnosed with breast cancer were included. Linear regression and χ2 analyses were conducted to examine aspects of oral health, using IBM SPSS Complex Samples software, version 27. Results: In our sample of 423 female breast cancer survivors, 7.1% were taking tamoxifen, 7.8% were taking anastrozole, 4.3% were taking letrozole, and 2.9% were taking exemestane. Compared with the survivors not taking such therapy, a greater proportion of those taking it had decayed teeth, gum disease/problems, and were recommended for imminent dental care after oral health examination by dentists. The survivors who were not taking adjuvant endocrine therapy had more coronal cavities. Conclusions: Data analysis showed that female breast cancer survivors taking adjuvant endocrine therapy appear more likely to have oral health issues than those not taking such therapy. Improved awareness of these issues is critical. Assessment and management guidelines to address these oral health issues are needed by health care providers. To learn more about the potential oral complications of adjuvant endocrine therapy in breast cancer survivors, the authors aimed to compare aspects of oral health in those who were taking the therapy with those who were not. [ABSTRACT FROM AUTHOR]

Background: This case series follows the relective processes undertaken, when ive slim women presented with reactive oedemas of the forearm and hand, that did not respond to usual therapy. Aim: To raise awareness about Aromatase Inhibitor (AI), Letrozole. Methods: Possible causes, including Cyclin-Dependent Kinase 4 and 6 (CDK4/6) inhibitors, Ribociclib and Axillary Web Syndrome, were explored and reviewed, and potential effective treatment options were then sought. New cases presented, which discounted each theory, until Letrozole was suspected. Results: Inlammatory oedemas were explained by the mechanisms-of-action relating to Aromatase Inhibitor Associated Musculoskeletal Syndrome (AIMSS), the severity of which, especially for slim women with oestrogen deprivation, causes almost 50% of women to cease treatment within 6 months; risking disease reoccurrence. Conclusion: Permissions were gained, a table was collated and sent to referring consultants, requesting risk/beneit analysis of Letrozole with a medication review. If non- responsive, inlammatory oedemas present in clinic, AIs should be considered as a trigger. [ABSTRACT FROM AUTHOR]

Endocrine therapy is one of the primary treatment methods for hormone receptor-positive breast cancer patients. As of June 1 2023, the National Medical Product Administration has approved 56 drugs related to endocrine therapy in patients with HR+ /HER-2- breast cancer (including generic drugs that have passed the consistency evaluation), including 44 endocrine drugs which can be categorized according to their mechanisms of action into selective estrogen receptor modulators, selective estrogen receptor down-regulators, aromatase inhibitors, luteinizing hormone-releasing hormone analogs, and progestogens and 12 targeted drugs for combined with endocrine therapy, including CDK4/6 inhibitors, mTOR inhibitors, and HDAC inhibitors. The different pharmacological characteristics, mechanisms of action, and long-term medication factors of breast cancer endocrine therapy-related drugs can directly affect patients′ medication adherence and medication safety. To standardize the pharmaceutical care of endocrine therapy drugs for breast cancer and promote rational use in clinical settings, the Oncology Specialty Pharmacist Subcommittee, in conjunction with multidisciplinary experts nationwide, has developed the "Guidelines for pharmaceutical care of endocrine therapy drugs for breast cancer (2023 edition)". The guidelines is based on clinical evidence-based evidence, relevant regulations of pharmaceutical management, and pharmaceutical care practices. The Delphi method and expert interviews were used to formulate the guidelines. The GRADE approach was used for assessing the certainty of evidence. This guideline mainly focuses on endocrine therapy for HR+ /HER-2- breast cancer patients. Due to space constraints, HER-2 positive targeted drugs were not included in the guideline. It covers 6 dimensions and 22 key problems of pharmaceutical care in the whole process of drug therapy, providing a scientific basis for pharmacists to carry out pharmaceutical care of such drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Estrogens, belonging to a group of steroid compounds, play an important role in both physiological and disease processes, mainly by interacting with estrogen receptors (ERs). Abnormal ER signaling may result in various cancers, including breast cancer (BC), one of the most often diagnosed cancers in women globally, and a second cause of female cancer-related death. In the present review, we discuss the current knowledge of the estrogen receptor-dependent signaling pathways in breast cancer. The significance of clinical implications of ER signaling in BC, including the potential therapies, is also summarized. Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors necessary for cancer invasion and dissemination. The significance of the clinical implications of ER signaling in BC, including the potential of endocrine therapies that target estrogens' synthesis and ER-dependent signal transmission, such as aromatase inhibitors or selective estrogen receptor modulators, is discussed. As a consequence, the challenges associated with the resistance to these therapies resulting from acquired ER mutations and potential strategies to overcome them are the critical point for the new treatment strategies' development. [ABSTRACT FROM AUTHOR]

The activation of male sexual behavior depends on brain estrogen synthesis. Estrogens act through nuclear and membrane receptors producing effects within hours/days or seconds/minutes, respectively. In mice, estrogen receptor alpha (ERα) is the main estrogen receptor (ER) controlling the activation of male sexual behavior. Although neuroestrogens rapidly modulate mouse sexual behavior, it is not known whether these effects involve membrane ERα (mERα). This study combines two complementary approaches to address this question. C451A‐ERα mice carry an ERα that cannot signal at the membrane, while estetrol (E4) is a natural estrogen acting as an agonist on nuclear ERα but as an antagonist on membrane ERα. In wild‐type males, E4 decreased the number of mounts and intromissions after 10 min. In C451A‐ERα males, E4 also altered sexual performance but after 30 min. E4 did not affect time spent near the female in both wild‐type and C451A‐ERα mice. However, regardless of genotype, the aromatase inhibitor 1,4,6‐Androstatriene‐3,17‐dione (ATD) decreased both sexual performance and the time spent near the female after 10 and 30 min, confirming the key role of aromatization in the rapid control of sexual behavior and motivation. In conclusion, the shift in timing at which the effect of E4 is observed in mice lacking mERα suggests a role for mERα in the regulation of rapid effects of neuroestrogens on sexual performance, thus providing the first demonstration that E4 acts as an antagonist of a mER in the brain. The persisting effect of ATD on behavior in C451A‐ERα mice also suggests the implication of another ER. [ABSTRACT FROM AUTHOR]

Aromatase inhibitors (Ais) are used as adjuvant endocrine therapy for oestrogen receptor‐positive (ER+ve) post‐menopausal breast cancer patients. Ais, by inhibiting the enzyme aromatase, block the conversion of androgen to oestrogen, reducing oestrogen levels. Resistance to Ais limits their clinical utilisation. Here, we show that overexpression of BQ323636.1 (BQ), a novel splice variant of nuclear co‐repressor NCOR2, is associated with resistance to the non‐steroidal aromatase inhibitor anastrozole in ER+ve post‐menopausal breast cancer. Mechanistic study indicates that BQ overexpression enhances androgen receptor (AR) activity and in the presence of anastrozole, causes hyper‐activation of AR signalling, which unexpectedly enhanced cell proliferation, through increased expression of CDK2, CDK4, and CCNE1. BQ overexpression reverses the effect of anastrozole in ER+ve breast cancer in an AR‐dependent manner, whilst co‐treatment with the AR antagonist bicalutamide recovered its therapeutic effect both in vitro and in vivo. Thus, for BQ‐overexpressing breast cancer, targeting AR can combat anastrozole resistance. Clinical study of 268 primary breast cancer samples of ER+ve patients who had been treated with non‐steroidal Ais showed 32.5% (38/117) of cases with combined high nuclear expression of BQ and AR, which were found to be significantly associated with Ai resistance. Non‐steroidal Ai‐treated patients with high nuclear expression of both BQ and AR had poorer overall, disease‐specific, and disease‐free survival. These findings suggest the importance of assessing BQ and AR expression status in the primary ER+ve breast tumour prior to Ai treatment. This may save patients from inappropriate treatment and enable effective therapy to be given at an early stage. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Testosterone therapy prompts the development of male secondary sexual characteristics coupled with numerous physiological changes; however, the effect of prolonged androgen exposure on transgender men's fertility remains to be fully elucidated. Multiple clinical consensuses advise assisted reproduction before hormone treatment and state that fertility preservation following androgen therapy entails the suspension of testosterone administration. Although the desire for reproduction among transgender men is prevalent, the discontinuation of gender-affirming hormone therapy poses a major challenge due to the anxiety, unease, and gender dysphoria that follow androgen withdrawal. The present investigation aimed to explore the feasibility and outcomes of oocyte retrieval in adult transgender men undergoing testosterone administration before or during fertility preservation. Seven case reports, four cohort studies, and two cross-sectional studies were identified following a systematic literature search on the PubMed/Ovid MEDLINE, Scopus, and ScienceDirect databases. The findings gathered in this review disclose the viability of oocyte retrieval after prolonged androgen exposure and suggest the absence of a direct relationship between the duration of testosterone suspension and fertility preservation outcomes. Although the reports are limited, recent evidence shows that continuous testosterone administration and the use of aromatase inhibitors during ovarian stimulation could potentially reduce the distressing effects of hormonal ovulation induction. New approaches to fertility preservation in transgender men must be further explored to ensure interventions aligned both with the reproductive desire and avoidance of gender dysphoria exacerbation that follow hormone therapy suspension. [ABSTRACT FROM AUTHOR]

Oestrogen synthesis pathway is one of the bottom line steps for breast cancer advancement; involving, aromatase enzyme (Cyp450), which transform androgens to oestrogens. Thus endocrine-based therapies comprising of human aromatase blockage is the most necessary way in order to decrease the oestrogen levels and thereafter prohibiting the chances of breast cancer commencement. In recent years, limelight on drug discovery from green sources has been growing for their less toxicity and cost effectiveness. Our present course of study aims at searching of new antagonist/s from a common dietary source "Citrus species". Molecular docking along with In-silico evaluation their pharmacokinetics (ADME) properties and toxicity were employed to fulfill the aim. Result shows that, all the five Citrus compounds have reasonable affinity towards cytochrome p450. However, Hesperidin shows highest affinity towards its target receptor protein i.e. -9.7 kcal/mol, followed by Chalcone that shows the lowest affinity towards its target protein i.e. -7.4 kcal/mol. Hence, bioactive components of Citrus species can be green alternatives for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Background Disparities in survival and clinical outcomes between African American and White patients with breast cancer (BC) are well documented, but African American patients have not been well represented in randomized clinical trials of CDK4/6 inhibitors. Real-world studies can provide evidence for effective treatment strategies for underreported patient populations. Patients and Methods This retrospective analysis of African American patients with HR+/HER2− metastatic breast cancer (mBC) from the Flatiron Health longitudinal database evaluated treatments for patients with BC in routine clinical practice in the US. Patients initiated first-line therapy with palbociclib plus an aromatase inhibitor (AI) or AI alone between February 2015 and March 2020. Outcomes assessed included overall survival (OS) and real-world progression-free survival (rwPFS) until September 2020. Results Of 270 eligible patients, 127 (median age 64 years) were treated with palbociclib + AI, and 143 (median age 68 years) were treated with an AI. Median follow-up was 24.0 months for palbociclib + AI and 18.2 months for AI-treated patients. Median OS was not reached (NR; 95% CI, 38.2-NR) in the palbociclib + AI group versus 28.2 months (95% CI, 19.2-52.8) in the AI group (adjusted HR, 0.56; 95% CI, 0.36-0.89; P  = .013). Median rwPFS was 18.0 months (95% CI, 12.4-26.7) in the palbociclib + AI group and 10.5 months (95% CI, 7.0-13.4) in the AI group (adjusted HR, 0.74; 95% CI, 0.47-1.17; P  = .199). Conclusion This comparative analysis of palbociclib + AI versus AI alone indicates that palbociclib combined with endocrine therapy in the first line is associated with improved effectiveness for African American patients with HR+/HER2− mBC in real-world settings. Trial number NCT05361655 [ABSTRACT FROM AUTHOR]

Abstract Background In oestrogen‐receptor positive breast cancer, daily oral adjuvant endocrine therapy (ET) for at least 5 years significantly reduces risks of recurrence and breast cancer‐specific mortality. However, many women are poorly adherent to ET. Development of effective adherence support requires comprehensive understanding of influences on adherence. We undertook an umbrella review to identify determinants of ET adherence. Methods We searched PubMed, Embase, CINAHL, PsycINFO, Cochrane and PROSPERO (inception to 08/2022) to identify systematic reviews on factors influencing ET adherence. Abstracted determinants were mapped to the World Health Organization's dimensions of adherence. Reviews were quality appraised and overlap assessed. Results Of 5732 citations screened, 17 reviews were eligible (9 quantitative primary studies; 4 qualitative primary studies; 4 qualitative or quantitative studies) including 215 primary papers. All five WHO dimensions influenced ET non‐adherence: The most consistently identified non‐adherence determinants were patient‐related factors (e.g. lower perceived ET necessity, more treatment concerns, perceptions of ET ‘cons’ vs. ‘pros’). Healthcare system/healthcare professional‐related factors (e.g. perceived lower quality health professional interaction/relationship) were also important and, to a somewhat lesser extent, socio‐economic factors (e.g. lower levels of social/economic/material support). Evidence was more mixed for medication‐related and condition‐related factors, but several may be relevant (e.g. experiencing side‐effects, cost). Potentially modifiable factors are more influential than non‐modifiable/fixed factors (e.g. patient characteristics). Conclusions The evidence‐base on ET adherence determinants is extensive. Future empirical studies should focus on less well‐researched areas and settings. The determinants themselves are numerous and complex in indicating that adherence support should be multifaceted, addressing multiple determinants.

In 2022, the global prevalence of erectile dysfunction (ED) was estimated to be at least 150 million cases. This number is greatly suspected to be underestimate as most men withhold information about ED. Also, about 15% of world population have infertility troubles, and male factors are responsible for almost half of these cases. Studies have shown that the quality of semen has decreased in the past several decades owing to various health factors and environmental toxicants. The current medical interventions involve the inhibition of phosphodiesterase 5 which suffer from serious side effects and costly. One of the popular and most sought interventions are the natural and nutritional remedies as they are foods in essence and potentially with no harm to the body. Therefore, the goal of this paper is to provide a review of the most common nutritional aphrodisiacs with increasing libido and fertility highlighting the potential active constituents as well as the underlying mechanisms.

PurposeRibociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).Patients and methodsPatients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods.ResultsThe intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96]. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI.ConclusionsRibociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).