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Lancet (London, England) Jan 2020Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period.
METHODS
IBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.
FINDINGS
3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105-156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39-0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27-0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45-0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33-0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22-0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78-0·65, p<0·0001). No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69-1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo). A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57-0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.
INTERPRETATION
This analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.
FUNDING
Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, Sanofi Aventis, and AstraZeneca.
Topics: Administration, Oral; Adult; Aged; Anastrozole; Aromatase Inhibitors; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Female; Follow-Up Studies; Humans; Incidence; Middle Aged; Placebos; Treatment Outcome; United Kingdom
PubMed: 31839281
DOI: 10.1016/S0140-6736(19)32955-1 -
Journal of Clinical Oncology : Official... Jun 2023Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS).
PATIENTS AND METHODS
This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818).
RESULTS
We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups.
CONCLUSION
Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.
Topics: Humans; Female; Anastrozole; Breast Neoplasms; Prospective Studies; Neoplasms, Second Primary; Nitriles; Triazoles; Neoplasm Recurrence, Local; Tamoxifen; Aromatase Inhibitors; Disease-Free Survival; Adjuvants, Immunologic; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant
PubMed: 37079878
DOI: 10.1200/JCO.22.00577 -
American Journal of Therapeutics 2020
Topics: Anastrozole; Drug Eruptions; Humans; Lichenoid Eruptions
PubMed: 33156584
DOI: 10.1097/MJT.0000000000001029 -
The Lancet. Oncology Jun 2023Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced... (Randomized Controlled Trial)
Randomized Controlled Trial
Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
BACKGROUND
Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting.
METHODS
DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment.
FINDINGS
Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes).
INTERPRETATION
Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape.
FUNDING
Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.
TRANSLATION
For the Chinese translation of the abstract see Supplementary Materials section.
Topics: Humans; Female; Breast Neoplasms; Letrozole; Anastrozole; Treatment Outcome; Disease-Free Survival; Receptor, ErbB-2; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method
PubMed: 37182538
DOI: 10.1016/S1470-2045(23)00172-9 -
The Lancet. Oncology Sep 2023The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of... (Randomized Controlled Trial)
Randomized Controlled Trial
Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.
BACKGROUND
The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer.
METHODS
In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete.
FINDINGS
Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction).
INTERPRETATION
Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials.
FUNDING
F Hoffmann-La Roche.
Topics: Humans; Female; Middle Aged; Anastrozole; Breast Neoplasms; Receptors, Estrogen; Neoadjuvant Therapy; Ki-67 Antigen
PubMed: 37657462
DOI: 10.1016/S1470-2045(23)00268-1 -
Molecular Cancer Therapeutics Jan 2022Our previous matched case-control study of postmenopausal women with resected early-stage breast cancer revealed that only anastrozole, but not exemestane or letrozole,...
Our previous matched case-control study of postmenopausal women with resected early-stage breast cancer revealed that only anastrozole, but not exemestane or letrozole, showed a significant association between the 6-month estrogen concentrations and risk of breast cancer. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor α. The mechanisms of endocrine resistance are heterogenous and with the new mechanism of anastrozole, we have found that treatment of anastrozole maintains fatty acid synthase (FASN) protein level by limiting the ubiquitin-mediated FASN degradation, leading to increased breast cancer cell growth. Mechanistically, anastrozole decreases the guided entry of tail-anchored proteins factor 4 (GET4) expression, resulting in decreased BCL2-associated athanogene cochaperone 6 (BAG6) complex activity, which in turn, prevents RNF126-mediated degradation of FASN. Increased FASN protein level can induce a negative feedback loop mediated by the MAPK pathway. High levels of FASN are associated with poor outcome only in patients with anastrozole-treated breast cancer, but not in patients treated with exemestane or letrozole. Repressing FASN causes regression of breast cancer cell growth. The anastrozole-FASN signaling pathway is eminently targetable in endocrine-resistant breast cancer.
Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Fatty Acid Synthases; Female; Humans
PubMed: 34667110
DOI: 10.1158/1535-7163.MCT-21-0509 -
The Australasian Journal of Dermatology May 2022
Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Dermatitis; Female; Humans; Nitriles
PubMed: 35196401
DOI: 10.1111/ajd.13813 -
Expert Opinion on Pharmacotherapy Sep 2002Anastrozole (Arimidex, AstraZeneca) is a third-generation aromatase inhibitor which rapidly reduces oestradiol concentrations to below detectable levels. It is both... (Review)
Review
Anastrozole (Arimidex, AstraZeneca) is a third-generation aromatase inhibitor which rapidly reduces oestradiol concentrations to below detectable levels. It is both potent and selective for the aromatase enzyme, with near-maximal suppression of serum oestrogens occurring at the clinical dose of 1 mg/day in postmenopausal women with advanced breast cancer. Anastrozole has also been shown to be a potent suppressor of intratumoural oestrogens, with responses comparable to those in serum. The results of two large, identically designed, randomised trials in postmenopausal women with advanced breast cancer who had progressed on tamoxifen showed that oral anastrozole 1 mg/day produced a statistically significant survival advantage over megestrol acetate 40 mg q.i.d. The median duration of survival was 26.7 months for anastrozole versus 22.5 months for megestrol acetate. Anastrozole was as well-tolerated as megestrol acetate, while weight gain was significantly increased in the megestrol acetate group compared with the anastrozole group. In another Phase III clinical trial involving 1021 postmenopausal women with advanced breast cancer, anastrozole showed a statistically significant advantage over tamoxifen in median time to progression in a combined analysis of 611 patients who were known to be oestrogen receptor- or progesterone receptor-positive. Anastrozole was as well-tolerated as tamoxifen, with a low rate of withdrawals (2%) due to drug-related adverse events. In addition, anastrozole was associated with fewer thromboembolic events and episodes of vaginal bleeding than tamoxifen. For women with hormone receptor-positive tumours who progress on tamoxifen, anastrozole is superior to megestrol acetate. In addition, anastrozole is a reasonable alternative to tamoxifen for first-line endocrine therapy of advanced breast cancer. Recent data confirm an emerging role for anastrozole as adjuvant therapy for primary breast cancer in postmenopausal patients. Anastrozole is also being investigated in the neoadjuvant setting.
Topics: Anastrozole; Animals; Breast Neoplasms; Disease Management; Drug Evaluation; Female; Humans; Nitriles; Survival Analysis; Triazoles
PubMed: 12186625
DOI: 10.1517/14656566.3.9.1329 -
American Journal of Health-system... Mar 1998The role of anastrozole, a new selective aromatase inhibitor, in treating hormone-responsive metastatic breast cancer is discussed. Treatment options for... (Review)
Review
The role of anastrozole, a new selective aromatase inhibitor, in treating hormone-responsive metastatic breast cancer is discussed. Treatment options for hormone-dependent breast cancer focus on interfering with the endocrine system in an attempt to modify the effects of estrogen. Tamoxifen is the drug of choice for primary endocrine therapy, but there is a need for agents with similar or greater efficacy and better tolerability. Anastrozole inhibits the conversion of androgens to estrogens by aromatase. Bioavailability studies have demonstrated almost complete absorption of anastrozole after oral administration. The drug's terminal half-life after multiple doses is 50 hours. Anastrozole is cleared principally by the liver. Clinical trials comparing anastrozole with megestrol acetate demonstrated no significant differences in clinical efficacy, although a follow-up study revealed a longer median overall survival rate in patients receiving anastrozole. The drug is well tolerated. Among the most frequently reported adverse effects are asthenia, hot flashes, headache, and back pain. The recommended dosage is 1 mg daily. The average wholesale cost of month's supply of anastrozole is $187.20, compared with approximately $100 for generic megestrol acetate or aminoglutethimide plus hydrocortisone. Although anastrozole will likely become the preferred second-line agent in the treatment of postmenopausal breast cancer in patients with disease progression after tamoxifen therapy, it is not a therapeutic alternative to aminoglutethimide on the basis of approved indications. Anastrozole and other aromatase inhibitors may have multiple applications in treating hormone-responsive breast cancer.
Topics: Anastrozole; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Estrogens; Female; Humans; Nitriles; Triazoles
PubMed: 9522927
DOI: 10.1093/ajhp/55.5.445 -
Breast Cancer Research and Treatment Apr 2020For patients with hormone receptor (HR)-positive advanced breast cancer, whether the combination of anastrozole and fulvestrant is more effective than anastrozole alone... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
For patients with hormone receptor (HR)-positive advanced breast cancer, whether the combination of anastrozole and fulvestrant is more effective than anastrozole alone is controversial. Our meta-analysis aimed to compare the efficacy and safety of the two therapies.
METHODS
We retrieved relevant studies in Embase, the Cochrane Library, Ovid MEDLINE, PubMed, ScienceDirect, Web of Science, Scopus, and Google Scholar. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The secondary outcomes were the disease control rate (DCR), the objective response rate (ORR), and adverse events (AEs).
RESULTS
Five articles based on 4 randomized controlled trials containing 2146 patients were identified in our meta-analysis. The combination group had better efficacy in the endpoints of OS (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.74-0.99, p = 0.03) and PFS (HR 0.87; 95% CI 0.77-0.97, p = 0.02). Regarding the ORR, DCR, total AEs and grade 3-5 AEs, we found no difference between the two treatments. The combination group showed a clearly higher rate of treatment discontinuations (95% CI 1.05-3.60, p = 0.03) and AEs leading to death (95% CI 1.12-9.11, p = 0.03). The subgroup analysis of AEs showed an increased incidence of extremity or muscle pain, hematologic effects, gastrointestinal disorders, and hot flashes in the combination group.
CONCLUSIONS
For HR-positive advanced breast cancer patients, the combination of anastrozole and fulvestrant appears to be superior to anastrozole alone in extending PFS and OS, despite relatively serious AEs.
Topics: Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fulvestrant; Humans; Prognosis; Randomized Controlled Trials as Topic; Survival Rate
PubMed: 32008124
DOI: 10.1007/s10549-020-05551-3