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American Journal of Respiratory and... May 2024Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models.
RATIONALE
Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models.
OBJECTIVES
We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH).
METHODS
We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters.
MEASUREMENTS AND MAIN RESULTS
Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups.
CONCLUSIONS
Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www.
CLINICALTRIALS
gov, ID: NCT03229499.
PubMed: 38747680
DOI: 10.1164/rccm.202402-0371OC -
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 -
Gan To Kagaku Ryoho. Cancer &... Apr 2024We report a case of right advanced breast cancer with multiple lung metastases in a 66-year-old woman. Her breast cancer( invasive ductal carcinoma, cT4bN1M1, Stage...
We report a case of right advanced breast cancer with multiple lung metastases in a 66-year-old woman. Her breast cancer( invasive ductal carcinoma, cT4bN1M1, Stage Ⅳ)was resected in October 2007(mastectomy plus axillary lymph node dissection)after local arterial infusion therapy(total dose 5-FU 4,735 mg plus adriamycin 180 mg), which caused bilateral lung arterial embolism due to deep vein thrombosis in right her leg. She had to be treated by anticoagulant therapy, mechanical ventilation and placement of IVC filter before her operation. Subsequent chemo-endocrine therapy(docetaxel 6 courses plus anastrozole)was continued. In October 2008, a CT scan showed disappearance of multiple lung metastases (complete response). In November 2015 (8 years after her operation), a CT scan showed recurrence of multiple lung metastases and endocrine therapy was changed to tamoxifen. A year later, a CT scan showed disappearance of multiple lung metastases(complete response)again and keep a condition of complete response in her breast cancer until May 2023 (15 years after her operation).
Topics: Humans; Female; Breast Neoplasms; Lung Neoplasms; Aged; Antineoplastic Combined Chemotherapy Protocols; Time Factors; Carcinoma, Ductal, Breast; Mastectomy
PubMed: 38644311
DOI: No ID Found -
Clinical Cancer Research : An Official... Jul 2024Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated...
PURPOSE
Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS.
PATIENTS AND METHODS
Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972).
RESULTS
Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS.
CONCLUSIONS
We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.
Topics: Humans; Female; Aromatase Inhibitors; Polymorphism, Single Nucleotide; Breast Neoplasms; Middle Aged; Aged; Prospective Studies; Anastrozole; Cohort Studies; Postmenopause; Aged, 80 and over; Patient Reported Outcome Measures; Aromatase
PubMed: 38640040
DOI: 10.1158/1078-0432.CCR-23-2137 -
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 -
Fertility and Sterility Jul 2024
Topics: Humans; Male; Testosterone; Luteinizing Hormone; Anastrozole; Infertility, Male; Nitriles; Triazoles; Aromatase Inhibitors; Semen Analysis; Semen; Treatment Outcome
PubMed: 38616033
DOI: 10.1016/j.fertnstert.2024.04.011 -
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 -
Practical Neurology Apr 2024In patients with ischaemic stroke, a carotid free-floating thrombus (CFFT) raises diagnostic and therapeutic challenges. We describe two women, each taking tamoxifen for...
In patients with ischaemic stroke, a carotid free-floating thrombus (CFFT) raises diagnostic and therapeutic challenges. We describe two women, each taking tamoxifen for invasive non-metastatic breast cancer, who developed large-vessel occlusion ischaemic strokes. The first had a CFFT 24 hours after receiving intravenous thrombolysis and mechanical thrombectomy; the thrombus completely resolved after 1 week of therapeutic anticoagulation. The second had a tandem occlusion with a CFFT at admission; her neurological deficits rapidly improved after intravenous thrombolysis without needing a mechanical thrombectomy. However, subsequently, under therapeutic anticoagulation, distal migration of the CFFT caused a recurrent large vessel occlusion ischaemic stroke, requiring mechanical thrombectomy. The CTFF in both cases appeared to relate to a cancer-related prothrombotic state. Both received long-term oral anticoagulation and their tamoxifen was switched to anastrozole. At 3 months, both were functionally independent without recurrent vascular events.
PubMed: 38575305
DOI: 10.1136/pn-2023-004061 -
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