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Frontiers in Oncology 2024Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular... (Review)
Review
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 advanced-stage 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.
PubMed: 38800404
DOI: 10.3389/fonc.2024.1385577 -
Pharmaceutics May 2024In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by...
Radiological and Molecular Analysis of Radioiodinated Anastrozole and Epirubicin as Innovative Radiopharmaceuticals Targeting Methylenetetrahydrofolate Dehydrogenase 2 in Solid Tumors.
In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by evaluating the potential of radioiodinated anastrozole ([I]anastrozole) and radioiodinated epirubicin ([I]epirubicin) as targeting agents against MTHFD2-driven tumors. MTHFD2, which is pivotal in one-carbon metabolism, is notably upregulated in various cancers, presenting a novel target for radiopharmaceutical application. Through molecular docking and 200 ns molecular dynamics (MD) simulations, we assess the binding efficiency and stability of [I]anastrozole and [I]epirubicin with MTHFD2. Molecular docking illustrates that [I]epirubicin has a superior binding free energy (∆) of -41.25 kJ/mol compared to -39.07 kJ/mol for [I]anastrozole and -38.53 kJ/mol for the control ligand, suggesting that it has a higher affinity for MTHFD2. MD simulations reinforce this, showing stable binding, as evidenced by root mean square deviation (RMSD) values within a narrow range, underscoring the structural integrity of the enzyme-ligand complexes. The root mean square fluctuation (RMSF) analysis indicates consistent dynamic behavior of the MTHFD2 complex upon binding with [I]anastrozole and [I]epirubicin akin to the control. The radius of gyration (RG) measurements of 16.90 Å for MTHFD2-[I]anastrozole and 16.84 Å for MTHFD2-[I]epirubicin confirm minimal structural disruption upon binding. The hydrogen bond analysis reveals averages of two and three stable hydrogen bonds for [I]anastrozole and [I]epirubicin complexes, respectively, highlighting crucial stabilizing interactions. The MM-PBSA calculations further endorse the thermodynamic favorability of these interactions, with binding free energies of -48.49 ± 0.11 kJ/mol for [I]anastrozole and -43.8 kJ/mol for MTHFD2-. The significant contribution of Van der Waals and electrostatic interactions to the binding affinities of [I]anastrozole and [I]epirubicin, respectively, underscores their potential efficacy for targeted tumor imaging and therapy. These computational findings lay the groundwork for the future experimental validation of [I]anastrozole and [I]epirubicin as MTHFD2 inhibitors, heralding a notable advancement in precision oncology tools. The data necessitate subsequent in vitro and in vivo assays to corroborate these results.
PubMed: 38794278
DOI: 10.3390/pharmaceutics16050616 -
Oncology Letters Jul 2024Invasive papillary carcinoma (IPC) of the breast is a rare form of cancer. The current report documents a case of IPC characterized by a large tumor size and skin...
Invasive papillary carcinoma (IPC) of the breast is a rare form of cancer. The current report documents a case of IPC characterized by a large tumor size and skin involvement. Surgical exploration revealed no evidence of axillary lymph node metastasis in breast cancer. Due to financial constraints, the patient opted solely for anastrozole endocrine therapy at a dosage of 1 mg/day for a period of 5 years post-surgery, foregoing other treatments such as radiotherapy and chemotherapy. Since discharge, 2.5 years have passed, during which the patient has been followed up via phone every 3 months, showing a good prognosis. A literature review indicated that IPC is prevalent amongst the elderly population and can be misdiagnosed due to its morphological, cytomorphological and immunophenotypic overlap with other types of papillary neoplasms. This tumor exhibits a more favorable prognosis compared with IDC, primarily attributed to its advantageous gene and molecular expression patterns, coupled with its decreased invasiveness. Despite limited evidence-based research on the treatment of IPC, the present case report, albeit with limitations, underscores the importance of avoiding over-treatment and suggests the feasibility of combining surgery with endocrine therapy for IPC.
PubMed: 38765791
DOI: 10.3892/ol.2024.14433 -
Translational Breast Cancer Research :... 2023We report a case of hormone receptor (HR) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer with multiple liver metastases who achieved...
BACKGROUND
We report a case of hormone receptor (HR) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer with multiple liver metastases who achieved good clinical benefit across cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine therapy. Prior to this, the patient underwent neoadjuvant therapy and surgery as well as adjuvant endocrine therapy. We present and discuss three important treatment decision nodes associated with it.
CASE DESCRIPTION
A 60-year-old woman was diagnosed with invasive ductal carcinoma of the left breast (cT4bN2M0, stage IIIB, Luminal B HER2-negative type) at the West China Hospital of Sichuan University in 2020, and received neoadjuvant chemotherapy and modified radical mastectomy of the left breast from 2020 to 2021. Postoperative radiotherapy was performed in the left chest wall and left upper and lower clavicular region. Adjuvant therapy is anastrozole endocrine therapy. Multiple liver metastases developed in 2022. The pathological molecular typing of liver metastases was confirmed to be consistent with the primary lesion. In the context of primary endocrine resistance, the first-line treatment of choice was fulvestrant in combination with a targeted CDK4/6 inhibitor (abemaciclib). This combination regimen made the liver metastases visibly shrunk, leading to partial response (PR) and has achieved a progression-free survival of 12 months. And there were no serious drug-related adverse events during first-line treatment.
CONCLUSIONS
CDK4/6 inhibitor is a promising antineoplastic agent for HR positive, HER2 negative breast cancer patients. With the development of research, the application scope of CDK4/6 inhibitors is gradually expanding, and the precision treatment of breast cancer requires more rational drug selection and combination.
PubMed: 38751470
DOI: 10.21037/tbcr-23-27 -
Annals of Oncology : Official Journal... May 2024In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone...
BACKGROUND
In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3.
PATIENTS AND METHODS
MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint.
RESULTS
A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed.
CONCLUSIONS
Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.
PubMed: 38729566
DOI: 10.1016/j.annonc.2024.04.013 -
Biomolecules Apr 2024Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron degenerative disease that is associated with demyelination. The () mouse exhibits motoneuron degeneration,...
Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron degenerative disease that is associated with demyelination. The () mouse exhibits motoneuron degeneration, gliosis and myelin deterioration in the cervical spinal cord. Since male s display low testosterone (T) levels in the nervous system, we investigated if T modified myelin-relative parameters in s in the absence or presence of the aromatase inhibitor, anastrozole (A). We studied myelin by using luxol-fast-blue (LFB) staining, semithin sections, electron microscopy and myelin protein expression, density of IBA1 microglia and mRNA expression of inflammatory factors, and the glutamatergic parameters glutamine synthetase (GS) and the transporter GLT1. Controls and + T showed higher LFB, MBP and PLP staining, lower g-ratios and compact myelin than s and + T + A, and groups showing the rupture of myelin lamellae. s showed increased IBA1 cells and mRNA for CD11b and inflammatory factors (IL-18, TLR4, TNFαR and PYR) vs. controls or + T. IBA1 cells, and CD11b were not reduced in + T + A, but inflammatory factors' mRNA remained low. A reduction of GS cells and GLT-1 immunoreactivity was observed in s and + T + A vs. controls and + T. Clinically, + T but not + T + A showed enhanced muscle mass, grip strength and reduced paw abnormalities. Therefore, T effects involve myelin protection, a finding of potential clinical translation.
Topics: Animals; Mice; Myelin Sheath; Amyotrophic Lateral Sclerosis; Male; Disease Models, Animal; Testosterone; Spinal Cord; Excitatory Amino Acid Transporter 2; Microglia
PubMed: 38672445
DOI: 10.3390/biom14040428 -
Frontiers in Endocrinology 2024The first phase of the GAIL study ("Girls treated with an Aromatase Inhibitor and Leuprorelin," ISRCTN11469487) has shown that the combination of anastrozole and...
Anastrozole monotherapy further improves near-adult height after the initial combined treatment with leuprorelin and anastrozole in early-maturing girls with compromised growth prediction: results from the second phase of the GAIL study.
BACKGROUND
The 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 HYPOTHESES
In 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.
METHODS
We 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 ( = 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 ( = 10) and group B ( = 20), who received only the combined treatment and leuprorelin alone, respectively, were recalled for evaluation of AH/NAH.
RESULTS
AH 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, = 0.01); group A2, +1.6 cm (+0.26 SDS, = 0.26); and group B, +1.7 cm (+0.3 SDS, = 0.08). The gain in group A1 was significantly greater than that in group A2 ( = 0.04) and in group B ( = 0.03). Anastrozole was determined to be safe even as monotherapy in Group A1.
CONCLUSIONS
In 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.
Topics: Female; Adult; Humans; Adolescent; Child; Anastrozole; Leuprolide; Aromatase Inhibitors; Puberty, Precocious; Puberty; Body Height
PubMed: 38628587
DOI: 10.3389/fendo.2024.1366970 -
Cancer Reports (Hoboken, N.J.) Apr 2024Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis,...
Drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method following mild COVID-19 in a patient under anastrozole therapy-A case report.
BACKGROUND
Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis, hypercholesterolemia, and musculoskeletal events, such as arthralgia and myalgia. Other adverse events are rare, including symptoms of acne, masculinization, and drug-induced liver injury, with the latter reported in a few cases only.
CASE
Here, we report on a patient under anastrozole therapy who developed drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method 5 weeks after a mild SARS-CoV-2 infection, which is, to the best of our knowledge, the first report of its kind involving anastrozole. Discontinuation of anastrozole resulted in a marked improvement of the alanine aminotransaminase, and aspartate aminotransaminase as well as normalized lactate dehydrogenase serum levels already seen after 26 days. Surprisingly, however, the cholestatic serum markers gamma-glutamyl transpeptidase and alkaline phosphatase showed a further rise, and took another 4 weeks to drop significantly.
CONCLUSION
The presentation of this case is meant to alert physicians to a potential drug-induced liver injury following mild SARS-CoV-2 infection in patients under anastrozole medication.
Topics: Humans; Anastrozole; COVID-19; SARS-CoV-2; Chemical and Drug Induced Liver Injury; Aromatase Inhibitors
PubMed: 38577842
DOI: 10.1002/cnr2.2028 -
Journal of Clinical Medicine Mar 2024Women are typically diagnosed with estrogen receptor-positive breast cancer around the postmenopausal period when declining estrogen levels initiate changes in lipid... (Review)
Review
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. Our meta-analysis was conducted on the lipid profiles of postmenopausal breast cancer patients at baseline and at different treatment time points. 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. 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.
PubMed: 38542042
DOI: 10.3390/jcm13061818 -
Analytical and Bioanalytical Chemistry May 2024Oral endocrine therapies (OET) for breast cancer treatment need to be taken over a long period of time and are associated with considerable side effects. Therefore,... (Comparative Study)
Comparative Study
Towards clinical adherence monitoring of oral endocrine breast cancer therapies by LC-HRMS-method development, validation, comparison of four sample matrices, and proof of concept.
Oral endocrine therapies (OET) for breast cancer treatment need to be taken over a long period of time and are associated with considerable side effects. Therefore, adherence to OET is an important issue and of high clinical significance for breast cancer patients' caregivers. We hypothesized that a new bioanalytical strategy based on liquid chromatography and high-resolution mass spectrometry might be suitable for unbiased adherence monitoring (AM) of OET. Four different biomatrices (plasma, urine, finger prick blood by volumetric absorptive microsampling (VAMS), oral fluid (OF)) were evaluated regarding their suitability for AM of the OET abemaciclib, anastrozole, exemestane, letrozole, palbociclib, ribociclib, tamoxifen, and endoxifen. An analytical method was developed and validated according to international recommendations. The analytical procedures were successfully validated in all sample matrices for most analytes, even meeting requirements for therapeutic drug monitoring. Chromatographic separation of analytes was achieved in less than 10 min and limits of quantification ranged from 1 to 1000 ng/mL. The analysis of 25 matching patient samples showed that AM of OET is possible using all four matrices with the exception of, e.g., letrozole and exemestane in OF. We were able to show that unbiased bioanalytical AM of OET was possible using different biomatrices with distinct restrictions. Sample collection of VAMS was difficult in most cases due to circulatory restraints and peripheral neuropathy in fingers and OF sampling was hampered by dry mouth syndrome in some cases. Although parent compounds could be detected in most of the urine samples, metabolites should be included when analyzing urine or OF. Plasma is currently the most suitable matrix due to available reference concentrations.
Topics: Humans; Female; Breast Neoplasms; Antineoplastic Agents, Hormonal; Drug Monitoring; Chromatography, Liquid; Administration, Oral; Mass Spectrometry; Letrozole; Medication Adherence; Limit of Detection; Tamoxifen; Saliva; Androstadienes; Anastrozole; Reproducibility of Results
PubMed: 38488952
DOI: 10.1007/s00216-024-05244-6