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Revista Da Associacao Medica Brasileira... Apr 2017Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of... (Review)
Review
Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.
Topics: Anastrozole; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemoprevention; Chemotherapy, Adjuvant; Female; Humans; Nitriles; Postmenopause; Reproducibility of Results; Tamoxifen; Treatment Outcome; Triazoles
PubMed: 28614542
DOI: 10.1590/1806-9282.63.04.371 -
Bulletin Du Cancer Oct 1999Aromatase inhibitors used in breast cancer, are drugs that inhibit the transformation of androstenedione and testosterone, respectively in estradiol and estrone. Two... (Review)
Review
Aromatase inhibitors used in breast cancer, are drugs that inhibit the transformation of androstenedione and testosterone, respectively in estradiol and estrone. Two classes have been described: steroidal inhibitors which act competitively and irreversibly and non steroidal inhibitors which block the P 450 cytochrome. The first one is aminoglutethimide which has an adrenal effect on 11, 18 and 21 hydroxylase. Rogletimide, less powerful and less specific is a aminoglutethimide analogue. The response rates obtained with formestane is not different. The clinical development has been stopped due to a lack of specificity. Letrozole, vorozole, exemestane and anastrozole are more powerful and more specific. Letrozole and vorozole are at least as efficient and better tolerated than aminoglutéthimide. Anastrozole, letrozole and vorozole are at least as efficient as megestrol acetate and better tolerated in advanced breast cancer patients receiving a second line hormone therapy.
Topics: Aminoglutethimide; Anastrozole; Androstadienes; Androstenedione; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Estrogen Antagonists; Estrone; Female; Humans; Letrozole; Nitriles; Triazoles
PubMed: 10572233
DOI: No ID Found -
Fertility and Sterility Oct 2023To identify patient factors associated with a clinically significant improvement in semen parameters among infertile men treated with the aromatase inhibitor anastrozole.
OBJECTIVE
To identify patient factors associated with a clinically significant improvement in semen parameters among infertile men treated with the aromatase inhibitor anastrozole.
DESIGN
Multi-institutional retrospective cohort study.
SETTING
Two Tertiary Academic Medical Centers.
PATIENTS
A total of 90 infertile men treated at 2 tertiary academic medical centers who met inclusion criteria and obtained pretreatment and posttreatment semen analyses.
INTERVENTION
Prescription of anastrozole (median 3 mg/wk).
MAIN OUTCOME MEASURES
Upgrade in the World Health Organization sperm concentration category (WHO-SCC). Univariate logistic regression, multivariable logistic regression, and partitioning analyses were performed to identify statistically significant patient factors capable of predicting treatment response.
RESULTS
With anastrozole treatment, 46% (n = 41/90) of men responded favorably with a WHO-SCC upgrade, and 12% (n = 11/90) experienced a downgrade. Responders exhibited lower pretreatment levels of luteinizing hormone (LH, 4.7 vs. 8.3 IU/L) and follicle-stimulating hormone (4.7 vs. 6.7 IU/mL), higher pretreatment levels of testosterone (T, 356 vs. 265 ng/dL), and similar baseline level of estradiol (E, 73% vs. 70% with detectible level). Baseline semen parameters differed, with anastrozole responders demonstrating higher baseline semen concentration (3.6 vs. 0.3 M/mL) and higher total motile sperm counts (3.7 vs. 0.1 M). Anastrozole therapy converted 29% (n = 26/90) of the cohort to normozoospermia and enabled intrauterine insemination access in 31% (n = 20/64) of previously ineligible patients. Interestingly, neither body mass index nor the baseline E level or E-T ratio was associated with WHO-SCC upgrade. Multivariable logistic regression revealed the T-LH ratio (odds ratio: 1.02, 95% confidence interval: 1.00-1.03) and baseline nonazoospermia (odds ratio: 9.4, 95% confidence interval: 1.1-78.9) to be statistically significant predictors of WHO-SCC upgrade (area under receiver operating characteristic curve: 0.77). The final user-friendly partitioning model consisting of the T-LH ratio ≥100 and baseline non-azoospermia was 98% sensitive and 33% specific for WHO-SCC upgrades (area under the curve: 0.77).
CONCLUSION
Anastrozole therapy decreases serum E levels, increases serum gonadotropins, and clinically improves semen parameters in half of men with idiopathic infertility. Nonazoospermic infertile men with T-LH ratios ≥100 are likely to benefit from anastrozole treatment irrespective of baseline E level or E-T ratio. Men with azoospermia rarely respond to anastrozole and should be counseled on alternative treatments.
Topics: Humans; Male; Anastrozole; Follicle Stimulating Hormone; Infertility, Male; Luteinizing Hormone; Retrospective Studies; Semen; Testosterone
PubMed: 37392782
DOI: 10.1016/j.fertnstert.2023.06.032 -
Breast (Edinburgh, Scotland) Dec 2023Preclinical data suggest synergistic activity with the combination of programmed death-1 and cyclin-dependent kinase 4/6 blockade in oestrogen receptor-positive/human...
Neoadjuvant nivolumab + palbociclib + anastrozole for oestrogen receptor-positive/human epidermal growth factor receptor 2-negative primary breast cancer: Results from CheckMate 7A8.
BACKGROUND
Preclinical data suggest synergistic activity with the combination of programmed death-1 and cyclin-dependent kinase 4/6 blockade in oestrogen receptor-positive/human epidermal growth factor 2-negative (ER+/HER2-) breast cancer. The noncomparative phase 1b/2 CheckMate 7A8 study (NCT04075604) evaluated neoadjuvant treatment with nivolumab, palbociclib, and anastrozole in patients with ER+/HER2- breast cancer. Here, we report outcomes from the safety run-in phase.
METHODS
Patients with histologically confirmed, untreated ER+/HER2- breast cancer, primary tumour ≥2 cm, ECOG performance status ≤1, and eligible for post-treatment surgery received nivolumab 480 mg intravenously every 4 weeks, palbociclib 125 mg or 100 mg orally once daily for 3 weeks per cycle, and anastrozole 1 mg orally once daily for five 4-week cycles, or until disease progression. The primary endpoint was the proportion of patients with dose-limiting toxicities (DLTs) within 4 weeks of treatment initiation.
RESULTS
At safety data review, 21 patients were treated (palbociclib 125-mg group: n = 9; palbociclib 100-mg group: n = 12). DLTs were reported in 2 (22.2%) and 0 patients in the palbociclib 125-mg and 100-mg groups, respectively. Across both groups, 9 patients discontinued treatment due to toxicity (grade 3/4 hepatic adverse events [n = 6], grade 3 febrile neutropaenia [n = 1], grade 1 pneumonitis [n = 1], and grade 3 rash and grade 2 immune-mediated pneumonitis [n = 1]). Consequently, the study was closed early.
CONCLUSIONS
Neoadjuvant treatment with nivolumab, palbociclib, and anastrozole showed a high incidence of grade 3/4 hepatotoxicity and treatment discontinuation, indicating that this combination should not be further pursued for treatment of primary ER+/HER2- breast cancer.
Topics: Female; Humans; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Neoadjuvant Therapy; Nivolumab; Pneumonia; Receptor, ErbB-2; Receptors, Estrogen
PubMed: 37741273
DOI: 10.1016/j.breast.2023.103580 -
Maturitas Nov 2015Testosterone (T) is the most abundant biologically active hormone in women. Androgen receptors (AR) are located throughout the body including the breast where T... (Review)
Review
Testosterone (T) is the most abundant biologically active hormone in women. Androgen receptors (AR) are located throughout the body including the breast where T decreases tissue proliferation. However, T can be aromatized to estradiol (E2), which increases proliferation and hence, breast cancer (BCA) risk. Increased aromatase expression and an imbalance in the ratio of stimulatory estrogens to protective androgens impacts breast homeostasis. Recent clinical data supports a role for T in BCA prevention. Women with symptoms of hormone deficiency treated with pharmacological doses of T alone or in combination with anastrozole (A), delivered by subcutaneous implants, had a reduced incidence of BCA. In addition, T combined with A effectively treated symptoms of hormone deficiency in BCA survivors and was not associated with recurrent disease. Most notably, T+A implants placed in breast tissue surrounding malignant tumors significantly reduced BCA tumor size, further supporting T direct antiproliferative, protective and therapeutic effect.
Topics: Anastrozole; Androgens; Aromatase; Aromatase Inhibitors; Breast; Breast Neoplasms; Drug Implants; Estrogens; Female; Humans; Nitriles; Testosterone; Triazoles
PubMed: 26160683
DOI: 10.1016/j.maturitas.2015.06.002 -
Clinical Pharmacology and Therapeutics Oct 2021Aromatase inhibitors (AIs) are the treatment of choice for hormone receptor-positive early breast cancer in postmenopausal women. None of the third-generation AIs are... (Randomized Controlled Trial)
Randomized Controlled Trial
Aromatase inhibitors (AIs) are the treatment of choice for hormone receptor-positive early breast cancer in postmenopausal women. None of the third-generation AIs are superior to the others in terms of efficacy. We attempted to identify genetic factors that could differentiate between the effectiveness of adjuvant anastrozole and exemestane by examining single-nucleotide polymorphism (SNP)-treatment interaction in 4,465 patients. A group of SNPs were found to be differentially associated between anastrozole and exemestane regarding outcomes. However, they showed no association with outcome in the combined analysis. We followed up common SNPs near LY75 and GPR160 that could differentiate anastrozole from exemestane efficacy. LY75 and GPR160 participate in epithelial-to-mesenchymal transition and growth pathways, in both cases with SNP-dependent variation in regulation. Collectively, these studies identified SNPs that differentiate the efficacy of anastrozole and exemestane and they suggest additional genetic biomarkers for possible use in selecting an AI for a given patient.
Topics: Anastrozole; Androstadienes; Antigens, CD; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Epithelial-Mesenchymal Transition; Female; Humans; Lectins, C-Type; Minor Histocompatibility Antigens; Neoplasm Staging; Patient Selection; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Treatment Outcome
PubMed: 34048027
DOI: 10.1002/cpt.2311 -
Polskie Archiwum Medycyny Wewnetrznej 2014In Western countries, breast cancer is the most common cancer in women but available interventions can reduce risk. The aim of the paper was to review the available... (Review)
Review
In Western countries, breast cancer is the most common cancer in women but available interventions can reduce risk. The aim of the paper was to review the available evidence regarding breast cancer chemoprevention trials. A systematic literature search was conducted to identify all full‑scale, randomized prospective chemoprevention trials as well as similarly conducted randomized trials with breast cancer as the primary monitoring endpoint. In full‑scale, randomized chemoprevention trials, the selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, reduce breast cancer incidence. In a direct comparison, tamoxifen resulted in greater breast cancer reduction than raloxifene but with greater endometrial cancer risk. The aromatase inhibitors, exemestane and anastrozole, also reduce breast cancer incidence in breast cancer prevention trials. In the Women's Health Initiative hormone therapy trials, in postmenopausal women with no prior hysterectomy, estrogen plus progestin increased breast cancer incidence and deaths from breast cancer, while estrogen alone, in women with prior hysterectomy, reduced breast cancer incidence and reduced deaths from breast cancer. For premenopausal women at increased breast cancer risk, tamoxifen is a proven option with favorable side effect profile. For postmenopausal women, while no direct comparison of SERMs and aromatase inhibitors for chemoprevention are available, cross‑study comparisons suggest greater efficacy and more favorable side effect profile for aromatase inhibitor use, especially for older women. The opposite effects of estrogen plus progestin compared with estrogen alone on breast cancer incidence and outcome should factor into risk‑benefit consideration when these agents are considered for climacteric symptom management.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemoprevention; Estrogen Antagonists; Estrogens; Female; Humans; Incidence; Nitriles; Postmenopause; Premenopause; Prospective Studies; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Tamoxifen; Treatment Outcome; Triazoles
PubMed: 24618912
DOI: 10.20452/pamw.2190 -
BMC Women's Health May 2021To study the effectiveness of an aromatase inhibitor (Anastrozole) associated with levonorgestrel-releasing intrauterine device (LNG-IUD, Mirena®) in the treatment of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To study the effectiveness of an aromatase inhibitor (Anastrozole) associated with levonorgestrel-releasing intrauterine device (LNG-IUD, Mirena®) in the treatment of endometriosis.
METHODS
Prospective, randomized clinical trial.
SETTING
University Hospital (single center). Elegibility criteria: Endometriomas > 3 × 4 cm, CA-125 > 35 U/mL and endometriosis symptoms.
PATIENTS
Thirty-one women randomized to anastrozole + Mirena® + Conservative Surgery(CS) (n = 8), anastrozole + Mirena® + transvaginal ultrasound-guided puncture-aspiration (TUGPA) (n = 7), Mirena® + CS (n = 9), or Mirena® + TUGPA (n = 7).
INTERVENTIONS
Anastrozole 1 mg/day and/or only Mirena® for 6 months; CS (ovarian and fertility-sparing) or TUGPA of endometriomas one month after starting medical treatment.
MAIN OUTCOME MEASURES
Visual analogic scale for symptoms, CA-125 levels, ultrasound findings of endometriomas and recurrences.
RESULTS
A significant improvement in symptoms during the treatment (difference of 43%, 95% CI 29.9-56.2) occurred, which was maintained at 1 and 2 years. It was more significant in patients including anastrozole in their treatment (51%, 95% CI 33.3-68.7). For CA-125, the most significant decrease was observed in patients not taking anastrozole (73.8%, 95% CI 64.2-83.4 vs. 53.8%, 95% CI 25.7-81.6 under Mirena® + anastrozole). After CS for endometriosis, a reduction of ultrasound findings of endometriomas and long-term recurrence occurred, with or without anastrozole. At 4.2 ± 1.7 years (95% CI 3.57-4.85), 88% of the patients who underwent CS were asymptomatic, without medication or reoperation, compared to only 21% if TUGPA was performed, with or without anastrozole (p = 0.019).
CONCLUSIONS
Dosing anastrozole for 6 months, starting one month before CS of endometriosis, reduces significantly the painful symptoms and delays recurrence, but has no other significant advantages over the single insertion of LNG-IUD (Mirena®) during the same time. Anastrozole and/or only Mirena® associated with TUGPA are not effective.
TRIAL REGISTRATION
Eudra CT System of the European Medicines Agency (London, 29-Sept-2008) Nº EudraCT: 2008-005744-17 (07/11/2008). Date of enrolment of first patient: 15/01/2009.
Topics: Anastrozole; Contraceptive Agents, Female; Endometriosis; Female; Humans; Intrauterine Devices; Intrauterine Devices, Medicated; Levonorgestrel; London; Prospective Studies
PubMed: 34016111
DOI: 10.1186/s12905-021-01347-9 -
British Journal of Clinical Pharmacology Dec 2010Little information is available regarding the metabolic routes of anastrozole and the specific enzymes involved. We characterized anastrozole oxidative and conjugation...
AIMS
Little information is available regarding the metabolic routes of anastrozole and the specific enzymes involved. We characterized anastrozole oxidative and conjugation metabolism in vitro and in vivo.
METHODS
A sensitive LC-MS/MS method was developed to measure anastrozole and its metabolites in vitro and in vivo. Anastrozole metabolism was characterized using human liver microsomes (HLMs), expressed cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs).
RESULTS
Hydroxyanastrozole and anastrozole glucuronide were identified as the main oxidative and conjugated metabolites of anastrozole in vitro, respectively. Formation of hydroxyanastrozole from anastrozole was markedly inhibited by CYP3A selective chemical inhibitors (by >90%) and significantly correlated with CYP3A activity in a panel of HLMs (r= 0.96, P= 0.0005) and mainly catalyzed by expressed CYP3A4 and CYP3A5. The K(m) values obtained from HLMs were also close to those from CYP3A4 and CYP3A5. Formation of anastrozole glucuronide in a bank of HLMs was correlated strongly with imipramine N-glucuronide, a marker of UGT1A4 (r= 0.72, P < 0.0001), while expressed UGT1A4 catalyzed its formation at the highest rate. Hydroxyanastrozole (mainly as a glucuronide) and anastrozole were quantified in plasma of breast cancer patients taking anastrozole (1 mg day⁻¹); anastrozole glucuronide was less apparent.
CONCLUSION
Anastrozole is oxidized to hydroxyanastrozole mainly by CYP3A4 (and to some extent by CYP3A5 and CYP2C8). Once formed, this metabolite undergoes glucuronidation. Variable activity of CYP3A4 (and probably UGT1A4), possibly due to genetic polymorphisms and drug interactions, may alter anastrozole disposition and its effects in vivo.
Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chromatography, Liquid; Cytochrome P-450 CYP3A; Female; Glucuronides; Glucuronosyltransferase; Humans; In Vitro Techniques; Metabolic Networks and Pathways; Microsomes, Liver; Nitriles; Oxidation-Reduction; Tandem Mass Spectrometry; Triazoles
PubMed: 21175441
DOI: 10.1111/j.1365-2125.2010.03791.x -
Translational Andrology and Urology Sep 2022Aromatase inhibitors (AIs), such as anastrozole, have shown effectiveness in treating oligoasthenozoospermia due to abnormal testosterone to estradiol (T/E) ratio (T/E...
BACKGROUND
Aromatase inhibitors (AIs), such as anastrozole, have shown effectiveness in treating oligoasthenozoospermia due to abnormal testosterone to estradiol (T/E) ratio (T/E <10). However, its efficacy in subfertile men without abnormal T/E ratio (T/E >10) remained unevaluated. This retrospective study aimed to investigate whether patients with T/E ratio >10 could also benefit from anastrozole treatment.
METHODS
One hundred and five subfertile patients treated with 1 mg anastrozole daily were included, in which 62 patients had a T/E ratio of <10, and 43 patients had this ratio >10. Semen parameters and sex hormone levels (including FSH, LH, PRL, E and total T) were measured before and after a three-month treatment. T/E ratio and total progressive motility sperm count were calculated from these results.
RESULTS
Patients in both groups (T/E ratio <10 and >10) showed significant increase in sex hormone levels (FSH, LH and total T), T/E ratio and semen parameters (semen volume, sperm concentration, total sperm count, progressive motility and total progressive motility count). The changes of these parameters between two groups were comparable. A subgroup analysis comparing the effect of anastrozole on overweight and normal patients also showed no significant difference. Improvements in semen parameters were seen in some azoospermic and cryptozoospermic patients.
CONCLUSIONS
The majority of subfertile men with and without abnormal T/E ratios responded to anastrozole treatment with significantly improved semen parameters and sex hormone levels. Anastrozole showed potential effectiveness in male subfertile patients with T/E >10, to be confirmed by future prospective, randomized, controlled studies.
PubMed: 36217397
DOI: 10.21037/tau-22-95