Anastrozole In Postmenopausal Patients Research Articles

Abstract OT2-04-02: CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer

Background: Programmed death-1 (PD-1) pathway inhibition has demonstrated clinical activity in breast cancer (BC), with modest response rate in advanced, heavily pretreated, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) BC. Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with estrogen receptor (ER) signaling blockade is an efficient treatment approach for patients with metastatic HR+/HER2− BC, evaluated in the primary setting. Preclinical data suggest potential synergistic activity of CDK 4/6 inhibition coupled with PD-1 blockade through modulation of the tumor microenvironment by the former modality. In a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with abemaciclib priming the immune response in phased administration of abemaciclib + anti-programmed death ligand 1 (PD-L1) therapy. Preliminary clinical data demonstrated activity of pembrolizumab + abemaciclib in a phase 1b study of pretreated patients with metastatic HR+, HER2− BC. Trial Design: CheckMate 7A8 is a randomized, noncomparative, multicenter, phase 2 study evaluating nivolumab + either abemaciclib or palbociclib + anastrozole in postmenopausal patients with ER+, HER2− primary BC. After determining safe doses for the nivolumab combination regimens in the safety run-in phase, patients will be randomized in a 4:4:3:4:4:3 ratio to 1 of 6 treatment arms (Table) stratified by PD-L1 expression (+ or −), node status (+ or −), and tumor size (> 3 cm or ≤ 3 cm). Following treatment, all patients will undergo surgery and safety follow-up. Eligible patients are postmenopausal women with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; with measurable disease based on RECIST v1.1; suitable for neoadjuvant endocrine monotherapy and surgery; have an ECOG PS of 0 or 1; have tumor tissue available at baseline; and are willing to undergo on-treatment research biopsy and tissue collection at surgery. Women of childbearing potential or who are breastfeeding, have a history of ipsilateral invasive BC regardless of treatment or DCIS treated with radiotherapy, metastatic disease, inflammatory/inoperable, multicentric, or bilateral invasive BC, or those suitable for neoadjuvant chemotherapy are excluded. Primary study endpoints are: i) number of patients with occurrence of dose-limiting toxicity (safety run-in phase), and ii) residual cancer burden (RCB) 0-I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, and objective response rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes in the tumor microenvironment, biomarkers predicting treatment sensitivity, changes in Ki67 levels, ER status and preoperative endocrine prognostic index score, and efficacy by PD-L1 status. Sample size was calculated assuming a 22% target RCB rate; 40 treated patients will provide 81% power at 10% 2-sided type I error to reject the null hypothesis that the true RCB rate is 8%, below which is not clinically meaningful. For primary and secondary endpoints, estimates of response rates and corresponding 95% confidence intervals will be generated for each arm using the Clopper-Pearson method. No patients have yet been recruited. For information, please contact Xiaochun.Liu@bms.com. Citation Format: Sara Tolaney, Guy Jerusalem, Roberto Salgado, Xiaochun Liu, Tian Chen, Hongxia Zhang, Mustimbo Roberts, Dimitrios Zardavas, Aleix Prat. CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-02.

Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor–Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial

Purpose The Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) -positive and node-positive early breast cancer (eBC). Methods Postmenopausal women with HR-positive and node-positive eBC were randomly assigned to receive adjuvant therapy with either letrozole (2.5 mg) or anastrozole (1 mg) once per day for 5 years or until recurrence of disease. Patients were stratified on the basis of the number of lymph nodes and human epidermal growth factor receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety. Results A total of 4,136 patients were randomly assigned to receive either letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709 DFS events (letrozole, 341 [16.5%]; anastrozole, 368 [17.7%]). The 5-year estimated DFS rate was 84.9% for letrozole versus 82.9% for anastrozole arm (hazard ratio, 0.93; 95% CI, 0.80 to 1.07; P = .3150). Exploratory analysis showed similar DFS with letrozole and anastrozole in all evaluated subgroups. The 5-year estimated overall survival rate was 89.9% for letrozole versus 89.2% for anastrozole arm (hazard ratio, 0.98; 95% CI, 0.82 to 1.17; P = .7916). Most common grade 3 to 4 adverse events (> 5% of patients) reported for letrozole versus anastrozole were arthralgia (3.9% v 3.3%, and 48.2% v 47.9% for all adverse events), hypertension (1.2% v 1.0%), hot flushes (0.8% v 0.4%), myalgia (0.8% v 0.7%), dyspnea (0.8% v 0.5%), and depression (0.8% v 0.6%). Conclusion Letrozole did not demonstrate significantly superior efficacy or safety compared with anastrozole in postmenopausal patients with HR-positive, node-positive eBC.

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial

Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0-2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637-0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83-20·99) in the fulvestrant group versus 13·8 months (11·99-16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. AstraZeneca.

Abstract PD2-01: Randomized phase 3 trial of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor positive, node positive early breast cancer: Final efficacy and safety results of the femara versus anastrozole clinical evaluation (Face) trial

Abstract Background The FACE trial was designed to evaluate the efficacy and safety of adjuvant letrozole (LET) versus anastrozole (ANA) in postmenopausal patients with hormone receptor-positive (HR+), node-positive breast cancer. Materials and methods In this phase 3b, open-label, multicenter trial, postmenopausal women with HR+ and lymph node positive breast cancer were randomized 1:1 to receive either LET (2.5 mg) or ANA (1 mg) daily for 5 years in the adjuvant setting. Randomization was stratified by the number of lymph nodes (1-3 versus 4+) and HER2 status (positive versus negative). Patients with stage IIA, IIB or IIIA invasive cancer were eligible. Treatment continued for 5 years or until disease recurrence. The primary endpoint was disease free survival (DFS) at 5 years. Key secondary endpoints were safety and overall survival (OS). Results Between Dec 2005 and Mar 2008, 4170 patients were randomized to receive LET (n = 2076) or ANA (n = 2094). Baseline characteristics were generally balanced between the two arms. Median age was 62 years; 71.4% of pts had 1-3+ lymph nodes, and 8.7% of cancers were HER2+. Median duration of exposure was 60 months in both arms. With 709 of the protocol-planned 959 DFS events, 5-yr estimated DFS rate was 84.9% for LET vs. 82.9% for ANA (HR = 0.93 [95% CI: 0.80 – 1.07]; p = 0.3150). 5-yr estimated OS rate was 89.9% for LET vs. 89.2% for ANA (HR = 0.98 [95% CI: 0.82 – 1.17]; p = 0.7916). Primary reasons for treatment discontinuation in the LET versus ANA arms were AEs (15.1% vs. 14.3%) and disease progression (9.5% vs. 10.4%). Safety profiles were similar between treatment arms. The most common adverse events (AEs) in the LET versus ANA arms were arthralgia (48.2% vs. 47.9%), hot flushes (32.5% vs. 32.3%) and fatigue (16.8% vs. 16.6%). Suspected drug-related grade 3/4 AEs were reported in 9.5% of patients in the LET arm versus 8.1% of patients in the ANA arm; suspected drug-related AEs leading to discontinuation were reported in 14.0% vs. 12.9% of patients in LET vs. ANA arms, respectively. Preplanned and exploratory subgroup analyses will be presented. Conclusions Treatment with LET did not demonstrate DFS efficacy difference over ANA in postmenopausal patients with HR+, node-positive breast cancer. (Funded by Novartis; ClinicalTrials.gov number NCT00248170). Citation Format: O'Shaughnessy J, Yardley DA, Burris HA, De Boer R, Amadori D, McIntyre K, Ejlertsen B, Gnant M, Jonat W, Pritchard KI, Dowsett M, Hart L, Poggio S, Valagussa P, Salomon H, Wamil B, Smith I. Randomized phase 3 trial of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor positive, node positive early breast cancer: Final efficacy and safety results of the femara versus anastrozole clinical evaluation (Face) trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD2-01.

Abstract OT3-2-03: An efficacy and safety trial of preoperative chemo-endocrine therapy in luminal B (HER2-negative) breast cancer: A prospective multi-institutional study

Abstract Background: The St.Gallen consensus guideline recommends the sequential administration chemotherapy followed by of endocrine therapy as postoperative therapy for the higher risk ER-positive breast cancer patients based on results of a single study (Albain et al, Lancet 2009). In metastatic settings however, several trials conducted in the 1980's demonstrated that tumor response rates were higher when chemotherapy and tamoxifen were concomitantly administered, than when chemotherapy and tamoxifen administered were given sequentially. In the preoperative settings, pathological complete response (pCR) rate can be used a surrogate marker to predict event-free survival or overall survival in Luminal B(HER2-negative) breast cancer. We therefore designed a prospective randomized safety and efficacy trial in order to test a hypothesis that the concomitant administration of an aromatase inhibitor and chemotherapy improves pathological complete response(pCR) rate than chemotherapy alone in the preoperative setting. Trial design: The trial is a prospective, multi-center, randomized comparison of chemotherapy alone versus concomitant chmo-endocrine therapy evaluating the efficacy in terms of pCR rate and safety in preoperative settings in patients with Luminal B (HER2-negative) breast cancer. 94 patients were to be accrued into this trial. - arm A (control): 12 cycles of weekly paclitaxel(80mg/m2) followed by 4 cycles of every 3-week AC(Doxorubicine 60mg/m2, Cyclophosphamide 600mg/m2). - arm B (experimental): The same chermotherapy as arm A and anastrozole in postmenopausal patients or anastrozole+leuprolerine in premenopansal patients. Eligibility criteria: 1)Female patients with operable and histologically confirmed invasive breast cancer; 2)HER2-negative; 3)Either ER -positive or PgR-positive; 4)Either Ki67-LI> = 14% and NG> = 2 or NG = 3 regardless of Ki67-LI. Endpoints : Primary endpoint is the pCR rate. Secondary endpoints are the clinical response rate(RECIST), the adverse events(CTC-AE ver.4.0), the breast conserving rate and the health related quality of life. Statistical Considerations : The pCR rates in the control arm and the experimental arm are expected to be 10% and 25%, respectively. In order to show the superiority of the experimental arm with an alfa error at 5% and beta error at 20%, calculated number of patients needed were 96. Present Accrual and Target Accrual: As of June 06, 2013, 18 patients were enrolled from 8 institutions. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-03.

The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial

Background:We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment.Methods:The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety.Results:In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P=0.02) and death (HR 0.45; P=0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P=0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P=0.68; distant recurrence-free survival HR 0.91; P=0.78; and OS HR 0.9; P=0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment (P=0.07).Conclusion:Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.

Estudo de custo-efetividade do anastrozol adjuvante no câncer de mama em mulheres pós-menopausa

Carry out an economic analysis of the incorporation of anastrozole as adjuvant hormone therapy in postmenopausal women with breast cancer in a Brazilian setting. The cost-effectiveness estimate comparing anastrozole to tamoxifen was made from the perspectives of the patient, private health insurance, and government. A Markov model was designed based on data from ATAC trial after 100 months follow-up in a hypothetical cohort of 1000 postmenopausal women in Brazil, using outcomes projections for a 25-year period. Resource utilization and associated costs were obtained from preselected sources and specialists' opinions. Treatment costs varied according to the perspective used. The incremental benefit was inserted in the model to obtain the cost of quality-adjusted life-year gained (QALY). Benefit extrapolations for a 25-year time line showed an estimate of 0.29 QALY gained with anastrozole compared to tamoxifen. The cost-effectiveness ratio per QALY gained depended on which perspective was used. There was an increment of R$ 32.403,00/QALY in the public health system/government, R$ 32.230,00/QALY for private health system, and R$ 55.270,00/QALY for patients. The benefit from adjuvant anastrozole in postmenopausal patients with breast cancer is associated to major differences in cost-effectiveness ratio and varies with the different perspectives. According to current WHO parameters, the increment is considered acceptable under public and private health system perspectives, but not from that of the patient.

Metastatic breast cancer: sequencing hormonal therapy and positioning of fulvestrant

Fulvestrant, a novel estrogen receptor (ER) antagonist with no agonist effects, binds, blocks, and degrades the ER, thereby downregulating cellular ER levels, which in turn leads to reduced expression of the progesterone receptor. Due to this specific working mechanism, fulvestrant is an important addition to the armamentarium of endocrine agents in advanced breast cancer (ABC). Fulvestrant has been shown to be equally effective as the third-generation aromatase inhibitor (AI) anastrozole in postmenopausal patients with hormone-sensitive ABC progressing prior to tamoxifen. In another randomized phase III trial, it was shown that fulvestrant had similar efficacy to tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive ABC. When comparing the side effects of fulvestrant with tamoxifen and anastrozole, it was shown that fulvestrant is well tolerated compared with these agents and is associated with a lower incidence of joint disorders. Clinical benefit on fulvestrant treatment after AI therapy has been reported in a substantial number of patients (28-46%). On the other hand, it was also shown that sensitivity to further endocrine therapy is retained following progression on first-line or second-line fulvestrant (57% and 46% clinical benefit, respectively). In conclusion, fulvestrant provides us with an additional endocrine treatment option making it possible to prolong the time that patients with ABC can be treated with endocrine therapy.

Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial

Some oestrogen-receptor (ER) positive breast cancers express epidermal growth factor receptor (EGFR), but whether inhibition of EGFR can suppress proliferation of breast cancer cells and ER function is not known. In a double-blind, placebo-controlled randomised trial of 56 postmenopausal patients with ER-positive and EGFR-positive primary breast cancer, 27 women were randomly assigned to the tyrosine-kinase inhibitor of EGFR gefitinib (250 mg given orally once a day) and the aromatase inhibitor anastrozole (1 mg given orally once a day), and 29 women to gefitinib (250 mg given orally once a day) and placebo of identical appearance to anastrozole given orally once a day, all given for 4-6 weeks before surgery. Primary outcome was inhibition of tumour-cell proliferation, as measured by Ki67 antigen labelling index. Secondary outcomes were reduction in EGFR phosphorylation at Tyr 845, reduction in ER phosphorylation at Ser 118, tumour size, and toxic effects. Analyses were by intention to treat. Patients assigned gefitinib and anastrozole had a greater reduction from pretreatment values in proliferation-related Ki67 labelling index than did those assigned gefitinib alone (mean % reduction 98.0 [95% CI 96.1-98.9] vs 92.4 [85.1-96.1]; difference between groups 5.6% [5.1-6.0], p=0.0054). Tumour size was reduced by 30-99% (partial response) in 14 of 28 patients assigned gefitinib and [corrected]in 12 of 22 assigned gefitinib, as assessed by ultrasonography. Reduction in phosphorylation of ER at Ser 118 was similar for both groups. Treatment was well tolerated and much the same for both groups. Single-agent gefitinib and gefitinib combined with anastrozole are well-tolerated and effective treatments for reducing the size of breast tumours and levels of ER phosphorylation when given as neoadjuvant therapy.

Biological activity of anastrozole in postmenopausal patients with advanced breast cancer: effects on estrogens and bone metabolism

BackgroundTo study the short-term biological effect of anastrozole on serum estrogens, androgens, 17-hydroxyprogesterone (17OH-PGR), gonadotrophins, sex hormone binding globulin (SHBG) and bone metabolism markers. Materials and methodsThirty-four consecutive patients with advanced breast cancer received anastrozole 1 mg/day. Blood samples were taken before commencement of treatment and at 2, 4, 8and 12 weeks during treatment to measure serum levels of estrogens (E1, E2 and E1-S), androgens [androstenedione (Δ4), dihydrotestosterone (DHT), testosterone (TST), free TST, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S)], 17OH-PGR, SHBG and gonadotrophins. As an indicator of bone resorption, we measured serum levels of C-terminal telopeptide of type I collagen (ICTP) and the cross-linked N-telopeptide of type I collagen (NTx), and for osteoblastic activity, intact osteocalcin (BGP) and bone alkaline phosphatase (BAP). ResultsAfter 2 weeks E1 and E1-S levels decreased on average by 56% (range 23.1–88.8%) and 75.8% (range 52.4–87.2%), respectively; E2 decreased on average by 62% (range 31.4–89.6%). No significant changes were detected in levels of androgens or 17OH-PGR. There was a significant increase in gonadotrophins over time (P = 0.0001 for both luteinizing hormone and follicle-stimulating hormone), and a significant decrease in SHBG (P = 0.0001). A progressive significant increase in bone metabolism serum markers was detected in all patients: BAP, P = 0.039; BGP, P = 0.016; ICTP, P = 0.0021; and NTx, P = 0.0013. In particular, patients with bone metastases had a statistically significant increase of bone resorption markers (ICTP, P = 0.0019; NTx, P = 0.025) and borderline for bone formation markers. In patients without bone disease, BAP, BGP and ICTP remained unchanged, whereas serum NTx significantly increased (P = 0.019). ConclusionsAnastrozole is a selective aromatase inhibitor as it does not modify serum levels of androgens and 17OH-PGR. In our experience no relationship was found in the short-term period between serum estrogen suppression and bone metabolism.

Anastrozole shows evidence of activity in postmenopausal patients who have responded or stabilised on formestane therapy

Formestane (Lentaron™) and anastrozole (Arimidex™) are in clinical use as second-line treatments for advanced breast cancer. Current practice is often to use an aromatase inhibitor only once before switching to third-line agents such as progestins. There are few clinical data on the sequential use of aromatase inhibitors. We therefore decided to study the clinical effects of anastrozole in postmenopausal patients with advanced breast cancer who had already received formestane. 21 patients were recruited. When receiving formestane 2/21 (10%) achieved a partial response (UICC criteria) and 10/21 (48%) stable disease. Of these 12 patients, 9 achieved further stable disease on anastrozole (78%; 7/9 oestrogen receptor positive). 4 of 9 patients who progressed on formestane also stabilised on anastrozole, of whom 3 had oestrogen receptor positive breast carcinomas. The explanation of this second stabilisation may relate to a further fall in oestradiol levels. We feel these results are of interest and warrant further clinical investigation.