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Journal of Human Genetics Jun 2013The most important modality of treatment in the two-thirds of patients with an estrogen receptor (ER)-positive early breast cancer is endocrine therapy. In... (Review)
Review
The most important modality of treatment in the two-thirds of patients with an estrogen receptor (ER)-positive early breast cancer is endocrine therapy. In postmenopausal women, options include the selective ER modulators (SERMs), tamoxifen and raloxifene, and the 'third-generation' aromatase inhibitors (AIs), anastrozole, exemestane and letrozole. Under the auspices of the National Institutes of Health Global Alliance for Pharmacogenomics, Japan, the Mayo Clinic Pharmacogenomics Research Network Center and the RIKEN Center for Genomic Medicine have worked collaboratively to perform genome-wide association studies (GWAS) in women treated with both SERMs and AIs. On the basis of the results of the GWAS, scientists at the Mayo Clinic have proceeded with functional genomic laboratory studies. As will be seen in this review, this has led to new knowledge relating to endocrine biology that has provided a clear focus for further research to move toward truly personalized medicine for women with breast cancer.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Genome-Wide Association Study; Humans; Japan; Letrozole; Musculoskeletal Physiological Phenomena; Nitriles; Pharmacogenetics; Phenotype; Postmenopause; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Tamoxifen; Triazoles
PubMed: 23635953
DOI: 10.1038/jhg.2013.35 -
Journal of Cancer Research and... Apr 2023Globally, cancer stands as the principle cause of mortality and immediate attention on its treatment options is required. Natural compounds stay at first priority in... (Observational Study)
Observational Study
CONTEXT
Globally, cancer stands as the principle cause of mortality and immediate attention on its treatment options is required. Natural compounds stay at first priority in encountering novel therapeutics without adverse effects.
AIM
The aim of the study is to extract flavonol quercetin from leafy vegetables of Anethum graveolens L. and Raphanus sativus L. and find out its potential in combination with drugs used for chemotherapy to reduce the adverse effects of drugs.
SETTINGS AND DESIGN
Observational study.
MATERIALS AND METHODS
Column chromatography is used for quercetin extraction and anticancer activity of quercetin + anastrozole and quercetin + capecitabine were determined by (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay (MTT), apoptosis assay, cell cycle analysis, mitochondrial membrane potential, and caspase 3 expression.
STATISTICAL ANALYSIS USED
Cytotoxic assay results were assessed by mean, standard deviation and ANOVA; and results were compared for determining its significance.
RESULTS
The results noted that quercetin at very less concentration (16 and 31 μg/ml on Michigan Cancer Foundation-7 and 43 and 46 μg/ml on COLO 320) in combination with anastrozole and capecitabine was able to control the growth of cells, increase cell death, arrest cell cycle, and induce mitochondrial depolarization and expression of caspase 3.
CONCLUSIONS
The natural compound used in the present study is effective in treating breast and colon cancer at minimal concentrations in combination with the drugs. This combinational treatment appears to be reported for the first time in the present study.
Topics: Humans; Quercetin; Capecitabine; Anastrozole; Caspase 3; Cell Proliferation; Apoptosis; Colonic Neoplasms; Cell Line, Tumor
PubMed: 37147989
DOI: 10.4103/jcrt.JCRT_599_20 -
Cancer Nov 2002The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and... (Review)
Review
BACKGROUND
The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles.
METHODS
In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane.
RESULTS
At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis.
CONCLUSIONS
All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Female; Humans; Letrozole; Nitriles; Triazoles
PubMed: 12404296
DOI: 10.1002/cncr.10908 -
Pharmaceutical Biology Dec 2018Psoralen and anastrozole are always used together for breast cancer patients in Chinese clinics.
CONTEXT
Psoralen and anastrozole are always used together for breast cancer patients in Chinese clinics.
OBJECTIVE
This study investigates the effects of psoralen on the pharmacokinetics of anastrozole in rats and its potential mechanism.
MATERIALS AND METHODS
The pharmacokinetics of orally administered anastrozole (0.5 mg/kg) with (test group) or without (Control group) psoralen pretreatment (20 mg/kg/day for 10 days) in male Sprague-Dawley rats (six rats in each group) were investigated. The plasma concentration of anastrozole was determined using a sensitive and reliable LC-MS/MS method. Additionally, the effects of psoralen on the intestine transport and metabolic stability of anastrozole (1 μM) were investigated using a Caco-2 cell transwell model and rat liver microsome incubation systems.
RESULTS
The results indicated that psoralen could significantly increase the C (from 56.74 ± 3.17 ng/mL to 83.26 ± 6.87 ng/mL), and t (from 10.80 ± 1.05 to 14.29 ± 1.38 h) of anastrozole (p < 0.05). Psoralen could also significantly decrease the efflux ratio of anastrozole from 1.88 to 1.32 (p < 0.05). Additionally, the intrinsic clearance rates of anastrozole decreased significantly (from 62.83 to 43.97 μL/min/mg protein) (p < 0.05) with psoralen pretreatment in rat liver microsome incubation systems.
DISCUSSION AND CONCLUSIONS
This study indicates that when the rats were pretreated with psoralen, the system exposure of anastrozole would be increased significantly. The results showed that the herb-drug interaction between psoralen and anastrozole might occur when they were co-administered, and future studies in humans also need to investigate its herb-drug interaction potential.
Topics: Anastrozole; Animals; Caco-2 Cells; Chromatography, Liquid; Drug Interactions; Ficusin; Humans; Male; Mass Spectrometry; Metabolic Clearance Rate; Microsomes, Liver; Rats; Rats, Sprague-Dawley
PubMed: 30345900
DOI: 10.1080/13880209.2018.1501584 -
British Journal of Cancer Mar 2011Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease.... (Review)
Review
Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; 'FACE-trial'), clinicians have to make their choices today. On the basis of available evidence summarised here and until FACE-data become available, letrozole seems to be the best choice for the majority of breast cancer patients whenever a non-steroidal aromatase inhibitor has to be chosen in a clinical setting. The background for this recommendation is discussed in the following chapters.
Topics: Anastrozole; Animals; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials, Phase III as Topic; Cytochrome P-450 CYP2D6; Female; Letrozole; Mice; Nitriles; Receptors, Estrogen; Receptors, Progesterone; Triazoles
PubMed: 21364577
DOI: 10.1038/bjc.2011.58 -
Oncotarget May 2014Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was... (Clinical Trial)
Clinical Trial
BACKGROUND
Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was investigated.
PATIENTS AND METHODS
We evaluated anastrozole and everolimus in 55 patients with metastatic estrogen (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates.
RESULTS
Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Twelve of 50 evaluable patients (24%) (median = 3 prior therapies) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR) (n = 5 (10%) with PR/CR): 9 of 32 (28%) with breast cancer (n=5 (16%) with PR/CR); 2 of 10 (20%), ovarian cancer; and 1 of 6 (17%), endometrial cancer. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway: mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All three responders (CR (n = 1); PR (n=2)) who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC.
CONCLUSIONS
Combination anastrozole and everolimus is well tolerated at full approved doses, and is active in heavily-pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Responses were observed in patients with multiple molecular aberrations. CLINICAL TRAILS INCLUDED: NCT01197170.
Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Genital Neoplasms, Female; Humans; Kaplan-Meier Estimate; Middle Aged; Nitriles; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Triazoles; Young Adult
PubMed: 24912489
DOI: 10.18632/oncotarget.1799 -
Clinical Cancer Research : An Official... Feb 2022Metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is an important cause of cancer mortality. Endocrine treatment with or without additional targeted... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is an important cause of cancer mortality. Endocrine treatment with or without additional targeted therapies has been the mainstay of treatment. This trial was designed to evaluate the combination of fulvestrant plus everolimus versus fulvestrant, everolimus, and anastrozole compared with fulvestrant alone in the first-line treatment of advanced HR-positive, HER2-negative breast cancer.
PATIENTS AND METHODS
This randomized placebo-controlled trial included postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no prior systemic therapy for metastatic disease. Participants were randomized to one of three treatment arms and the primary outcome was progression-free survival (PFS), comparing combinations of fulvestrant and everolimus with or without anastrozole with fulvestrant alone. Circulating tumor cells (CTC), as measured with two different methods, and circulating tumor DNA (ctDNA) were evaluated serially prior to treatment and the beginning of the second cycle of therapy.
RESULTS
Due in part to changes in clinical practice, the study was closed after accruing only 37 participants. There was no evidence that everolimus-containing combination treatment improved PFS or overall survival relative to fulvestrant alone. When modeled continuously, an association was observed of baseline CTC and ctDNA with poorer survival.
CONCLUSIONS
Although power of the study was limited, the findings were unable to support the routine use of everolimus combination endocrine therapy in the first-line treatment of advanced hormone-sensitive breast cancer. Prognostic impact of baseline ctDNA and copy-number variations in CTC was demonstrated.
Topics: Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Fulvestrant; Humans; Receptor, ErbB-2; Receptors, Estrogen
PubMed: 34844978
DOI: 10.1158/1078-0432.CCR-21-3131 -
Clinical Cancer Research : An Official... Jun 2020To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast...
PURPOSE
To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs.
EXPERIMENTAL DESIGN
Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays.
RESULTS
Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk ( = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold ( = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient T47D breast cancer cell line.
CONCLUSIONS
This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.
Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Case-Control Studies; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Estrogen Receptor alpha; Estrogens; Female; Follow-Up Studies; Humans; Middle Aged; Multicenter Studies as Topic; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 32098767
DOI: 10.1158/1078-0432.CCR-19-3091 -
JAMA Oncology Jul 2022Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and Efficacy of the mTOR Inhibitor, Vistusertib, Combined With Anastrozole in Patients With Hormone Receptor-Positive Recurrent or Metastatic Endometrial Cancer: The VICTORIA Multicenter, Open-label, Phase 1/2 Randomized Clinical Trial.
IMPORTANCE
Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives hormonal resistance, thus supporting the rationale of combining mTOR inhibitor with endocrine therapy.
OBJECTIVE
To evaluate the safety and efficacy of vistusertib in combination with anastrozole in the treatment of women with hormone receptor-positive recurrent or metastatic endometrial cancer.
DESIGN, SETTINGS, AND PARTICIPANTS
The VICTORIA study was a multicenter, open-label, randomized clinical trial that accrued 75 patients with hormone receptor-positive recurrent or metastatic endometrial cancer from 12 cancer centers in France in April 2016 to October 2019. After a safety run-in period, a Simon 2-stage design was used. Data analyses were performed from December 11, 2020, to March 11, 2021.
INTERVENTIONS
Patients were randomized in a 2:1 ratio to oral vistusertib (125 mg twice daily 2 days per week) and oral anastrozole (1 mg daily) in the combination vistusertib with anastrozole arm (V+A arm) or oral anastrozole alone (A arm).
MAIN OUTCOMES AND MEASURES
The primary end point was serious adverse events for the safety run-in period and progression-free rate at 8 weeks (8wk-PFR)-assessed with a blinded independent central review in phase 2. The secondary end points were objective response rate, duration of response, progression-free survival (PFS), overall survival, and incidence of adverse events.
RESULTS
Of the 75 patients who were randomized, 73 (median [range] age, 69.5 [37-88] y; all female) were treated: V+A arm, 49 patients; A arm, 24 patients. In the V+A arm, the 8wk-PFR was 67.3% (unilateral 95% CI, 54.7%) and in the A arm, 39.1% (unilateral 95% CI, 22.2%). No significant serious adverse events were reported during the safety run-in period (n = 6 in V+A arm). The overall response rate was 24.5% (95% CI, 13.3%-38.9%) in the V+A arm vs 17.4% (95% CI, 5.0%-38.8%) in the A arm. With a median follow-up of 27.7 months, median PFS was 5.2 (95% CI, 3.4-8.9) in the V+A arm and 1.9 (95% CI, 1.6-8.9) months in the A arm. Fatigue, lymphopenia, hyperglycemia, and diarrhea were the most common (grade ≥2) adverse events associated with vistusertib.
CONCLUSIONS AND RELEVANCE
This multicenter, open-label, phase 1/2 randomized clinical trial demonstrated that adding vistusertib to anastrozole improved 8wk-PFR, overall response rate, and PFS for patients with endometrial cancer and had manageable adverse events. Identification of molecular subgroups would allow for more precise selection of patients who may be most likely to experience favorable outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02730923.
Topics: Aged; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Breast Neoplasms; Endometrial Neoplasms; Female; Humans; MTOR Inhibitors; Morpholines; Phosphatidylinositol 3-Kinases; Pyrimidines; TOR Serine-Threonine Kinases
PubMed: 35551299
DOI: 10.1001/jamaoncol.2022.1047 -
The Journal of Clinical Endocrinology... Apr 2022Currently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane,...
CONTEXT
Currently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane, and the ultra-low levels of estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing a liquid chromatography-tandem mass spectrometry (MS/MS) method for simultaneous assessment of letrozole, anastrozole, exemestane, and 17-hydroxyexemestane as well as subpicomolar levels of estradiol and estrone.
METHODS
Internal standards, calibrators, serum samples, and quality controls were in fully automated steps transferred to a deep-well plate for a 2-step liquid-liquid extraction. The extracts were reconstituted and analytes were separated chromatographically using 2 serially coupled columns, then subject to MS/MS in electrospray ionization mode. The method was thoroughly validated and is traceable to 2 accredited estrogen methods.
RESULTS
The measurement range for estrone and estradiol was 0.2 to 12 000 pmol/L and 0.8 to 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had a precision of less than or equal to 13%, and accuracies within 100 ± 8%. As proof of concept, AI and estrogen levels were determined in serum samples from postmenopausal breast cancer patients under treatment.
CONCLUSION
We present here an assay suitable for the simultaneous measurement of serum levels of all third-generation AIs and ultra-low levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below the threshold of detection for most routine assays, but still require suppression.
Topics: Anastrozole; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Estradiol; Estrogens; Estrone; Female; Humans; Letrozole; Nitriles; Postmenopause; Tandem Mass Spectrometry
PubMed: 34958096
DOI: 10.1210/clinem/dgab923