Search

This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (−11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (−10.68 kcal/mol) and the co-crystallized ligand (−9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (−23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (−20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (−16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment. [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]

Abstract Purpose The effectiveness of anastrozole for breast cancer prevention has been demonstrated. The objective of this study was to evaluate the cost-effectiveness of anastrozole for the prevention of breast cancer in women with a high risk of breast cancer and to determine whether anastrozole for the primary prevention of breast cancer can improve the quality of life of women and save health-care resources. Methods A decision-analytic model was used to assess the costs and effects of anastrozole prevention versus no prevention among women with a high risk of breast cancer. The key parameters of probability were derived from the IBIS-II trial, and the cost and health outcome data were derived from published literature. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for the two strategies,One-way and probabilistic sensitivity analyses were performed. Results In the base case, the incremental cost per QALY of anastrozole prevention was £125,705.38/QALY in the first 5 years compared with no prevention in the UK, above the threshold of WTP (£3,000/QALY),and in the 12-year period, the ICER was £8,313.45/QALY, less than WTP. For the US third-party payer, ICER was $134,232.13/QALY in the first 5 years and $8,843.30/QALY in the 12 years, both less than the WTP threshold ($150,000/QALY). Conclusion In the UK and US, anastrozole may be a cost-effective strategy for the prevention of breast cancer in high-risk postmenopausal women. Moreover, the longer the cycle of the model, the higher the acceptability. The results of this study may provide a scientific reference for decision-making for clinicians, patients, and national medical and health care government departments.

Background: Women are typically diagnosed with estrogen receptor-positive breast cancer around the postmenopausal period when declining estrogen levels initiate changes in lipid profiles. Aromatase inhibitors (AI) are used to prevent the progression of cancer; however, a further reduction in estrogen levels may have detrimental effects on lipid levels, which was our working hypothesis. Methods: Our meta-analysis was conducted on the lipid profiles of postmenopausal breast cancer patients at baseline and at different treatment time points. Results: We identified 15 studies, including 1708 patients. Studies using anastrozole (ANA), exemestane (EXE), letrozole (LET), and tamoxifen (TMX) were involved. Subgroup analyses revealed that 3- and 12-month administrations of LET and EXE lead to negative changes in lipid profiles that tend to alter the lipid profile undesirably, unlike ANA and TMX. Conclusions: Our results suggest that, despite statistically significant results, EXE and LET may not be sufficient to cause severe dyslipidemia in patients without cardiovascular comorbidities according to the AHA/ACC Guideline on the Management of Blood Cholesterol. However, the results may raise the question of monitoring the effects of AIs in patients, especially those with pre-existing cardiovascular risk factors such as dyslipidemia. [ABSTRACT FROM AUTHOR]

This study examines the intricate relationship between protein glycosylation dynamics and therapeutic responses in Luminal A and Luminal B breast cancer subtypes, focusing on anastrozole and tamoxifen impacts. The present methods inadequately monitor and forecast patient reactions to these treatments, leaving individuals vulnerable to the potential adverse effects of these medications. This research investigated glycan structural changes by following patients for up to 9 months. The protocol involved a series of automated steps including IgG isolation, protein denaturation, glycan labelling, purification, and final analysis using capillary gel electrophoresis with laser-induced fluorescence. The results suggested the significant role of glycan modifications in breast cancer progression, revealing distinctive trends in how anastrozole and tamoxifen elicit varied responses. The findings indicate anastrozole's association with reduced sialylation and increased core fucosylation, while tamoxifen correlated with increased sialylation and decreased core fucosylation. These observations suggest potential immunomodulatory effects: anastrozole possibly reducing inflammation and tamoxifen impacting immune-mediated cytotoxicity. This study strongly emphasizes the importance of considering specific glycan traits to comprehend the dynamic mechanisms driving breast cancer progression and the effects of targeted therapies. The nuanced differences observed in glycan modifications between these two treatments underscore the necessity for further comprehensive research aimed at thoroughly evaluating the long-term implications and therapeutic efficacy for breast cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: The effectiveness of anastrozole for breast cancer prevention has been demonstrated. The objective of this study was to evaluate the cost-effectiveness of anastrozole for the prevention of breast cancer in women with a high risk of breast cancer and to determine whether anastrozole for the primary prevention of breast cancer can improve the quality of life of women and save health-care resources. Methods: A decision-analytic model was used to assess the costs and effects of anastrozole prevention versus no prevention among women with a high risk of breast cancer. The key parameters of probability were derived from the IBIS-II trial, and the cost and health outcome data were derived from published literature. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for the two strategies,One-way and probabilistic sensitivity analyses were performed. Results: In the base case, the incremental cost per QALY of anastrozole prevention was £125,705.38/QALY in the first 5 years compared with no prevention in the UK, above the threshold of WTP (£3,000/QALY),and in the 12-year period, the ICER was £8,313.45/QALY, less than WTP. For the US third-party payer, ICER was $134,232.13/QALY in the first 5 years and $8,843.30/QALY in the 12 years, both less than the WTP threshold ($150,000/QALY). Conclusion: In the UK and US, anastrozole may be a cost-effective strategy for the prevention of breast cancer in high-risk postmenopausal women. Moreover, the longer the cycle of the model, the higher the acceptability. The results of this study may provide a scientific reference for decision-making for clinicians, patients, and national medical and health care government departments. [ABSTRACT FROM AUTHOR]