VA Class:AN900
Anastrozole, an aromatase inhibitor, is an antineoplastic agent.1
Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer
Anastrozole is used alone as initial (primary) adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer.1 Anastrozole also is used as sequential adjuvant therapy following 2-3 years of adjuvant tamoxifen for early-stage hormone receptor-positive breast cancer in postmenopausal women51,52,53,63,64,65,78,10019,10053,10075 and as extended adjuvant therapy following adjuvant tamoxifen for hormone receptor-positive early-stage breast cancer in postmenopausal women.54,75,81,10019
Clinical Experience as Initial Adjuvant Therapy
In a double-blind, multicenter trial (the Arimidex, Tamoxifen, Alone or in Combination [ATAC] trial), 9366 postmenopausal women with operable breast cancer were randomized to receive anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of anastrozole 1 mg daily and tamoxifen 20 mg daily, as adjuvant therapy for 5 years or until recurrence of disease.1,24 About 84% of the patients in each group had hormone receptor-positive (i.e., estrogen receptor-positive, progesterone receptor-positive, or both) breast tumors.1,24 The primary end point of the trial was disease-free survival, which was defined as time to occurrence of any of the following events: distant or local recurrence, a contralateral primary breast tumor, or death from any cause.1
Analysis of the data at a median follow-up of 68 months, when patients had received treatment for a median of 60 months, showed that disease-free survival was prolonged in patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio of 0.87 with a 95% confidence interval of 0.78-0.97).1,50 The frequency of events observed in patients receiving anastrozole versus tamoxifen was locoregional recurrence in 3.8 versus 4.8%, contralateral breast cancer in 1.1 versus 1.9%, and distant recurrence in 10.4 versus 12% of patients.1 No difference was observed between the groups for the secondary endpoints of distant disease-free survival and overall survival.1,50 Subgroup analysis confirmed that disease-free survival was prolonged with anastrozole versus tamoxifen therapy for patients with hormone receptor-positive tumors, but benefit was less clear in patients who had received previous adjuvant therapy or patients who were 65 years of age or older.1
Analysis of the data (both overall and for the subset of patients with hormone receptor-positive tumors) at a median follow-up of 10 years (120 months) showed that the benefit of prolonged disease-free survival was maintained in patients receiving anastrozole, but there was no difference in overall survival between the groups;1,66 time to recurrence, time to distant recurrence, and incidence of contralateral breast cancer also were improved in patients receiving anastrozole compared with those receiving tamoxifen.66 The greatest differences between anastrozole and tamoxifen in time to recurrence, rate of contralateral breast cancer, and disease-free survival were observed during the first 2 years of treatment; between-treatment differences in distant recurrence rates remained similar over 10 years of follow-up.66 Although recurrence rates for the anastrozole and tamoxifen treatment groups remained different throughout 10 years of follow-up, analyses conducted using data for patients with hormone receptor-positive tumors suggested that the difference between treatments might diminish after 8 years of follow-up.66 Assessment of quality of life during 5 years of treatment did not show any difference between the anastrozole and tamoxifen groups.57,68
At a median follow-up of 33 months, combination therapy with anastrozole and tamoxifen was not associated with an improvement in disease-free survival compared with tamoxifen alone, and this treatment arm was discontinued.1,24
In the ATAC trial, anastrozole was associated with a higher incidence of joint disorders (including arthritis, arthrosis, and arthralgia), fractures (including fractures of the spine, hip, and wrist), and elevations in serum cholesterol compared with tamoxifen.1 Anastrozole was associated with a lower incidence of endometrial cancer, ischemic cerebrovascular events, venous thromboembolic events (including deep venous thrombosis), vaginal discharge, vaginal bleeding, and hot flushes compared with tamoxifen.1,50
Trials comparing anastrozole to other aromatase inhibitors (i.e., letrozole, exemestane) for initial adjuvant therapy in postmenopausal women with hormone receptor-positive early breast cancer have found no significant differences in survival outcomes.10002,10029
Clinical Experience as Sequential Adjuvant Therapy
In a randomized trial involving 448 postmenopausal women with node-positive, estrogen receptor-positive breast cancer (Italian Tamoxifen Anastrozole [ITA] trial), patients who had received 2-3 years of adjuvant tamoxifen therapy were randomized to receive anastrozole or to continue receiving tamoxifen to complete a total of 5 years of adjuvant therapy.51 At a median follow-up of 36 months following randomization, those receiving tamoxifen followed by anastrozole had longer event-free survival and disease-free survival but similar overall survival as those receiving 5 years of tamoxifen therapy.51 Improvements in recurrence-free survival and event-free survival associated with anastrozole therapy were maintained at median follow-up times of 64 and 128 months; overall survival was not significantly different between treatment groups.63,78
Analysis of combined data from 2 randomized trials involving a total of 3224 postmenopausal women with hormone-sensitive early-stage breast cancer who had received 2 years of adjuvant therapy with tamoxifen (Austrian Breast and Colorectal Cancer Study Group trial 8 [ABCSG-8] and Arimidex-Nolvadex [ARNO] 95 trial) showed that those receiving anastrozole for the remaining 3 years of adjuvant therapy had a higher rate of event-free survival (96%) compared with those receiving tamoxifen for the entire 5-year period (93%); at the completion of 5 years of endocrine therapy, overall survival did not differ between the groups.52 Analysis of data from ABCSG-8 alone showed a low overall rate of breast cancer recurrence and a high overall survival rate among patients enrolled in this study (reflecting inclusion in the study of women at low to moderate risk of recurrence) and no significant difference in recurrence-free survival between the 2 adjuvant regimens at a median follow-up of 5 years after initiation of adjuvant endocrine therapy.64 Analysis of data from the ARNO 95 trial at a median follow-up of 30 months, when patients who previously had received tamoxifen for 2 years had received randomized treatment with anastrozole or tamoxifen for a median of about 27 months, indicated that patients who were switched to anastrozole had prolonged disease-free and overall survival compared with those who continued receiving tamoxifen.65
Analysis of pooled data53 for individual patients from these 3 randomized trials,51,52,64 conducted at a median follow-up of 30 months, suggested that disease-free survival, event-free survival, distant recurrence-free survival, and overall survival are longer in patients who switch to anastrozole following 2-3 years of tamoxifen than in those who remain on tamoxifen for the 5-year duration of adjuvant therapy for hormone receptor-positive early-stage breast cancer.
Sequential Versus Initial Adjuvant Therapy
The efficacy of anastrozole and other aromatase inhibitors as sequential therapy following tamoxifen or as initial therapy was evaluated in a multicenter, open-label, randomized trial (FATA-GIM30).10053 Postmenopausal women with surgically resected hormone receptor-positive breast cancer were randomly assigned to treatment with either anastrozole 1 mg once daily, exemestane 25 mg once daily, or letrozole 2.5 mg once daily; these treatments were given as initial therapy for 5 years or as sequential therapy for 3 years following 2 years of treatment with tamoxifen 20 mg once daily.10053 A total of 3697 patients were enrolled and followed for a median of 60 months.10053 The primary outcome was disease-free survival.10053 At 5 years, disease-free survival was similar between the initial and sequential regimens (89.8 versus 88.5%, respectively).10053 The secondary outcome of overall survival was also similar between the initial and sequential regimens (96.8 versus 95.3%, respectively).10053 Comparisons between the 3 aromatase inhibitors found 5-year disease-free survival rates of 90.0, 88.0, and 89.4% with anastrozole, exemestane, and letrozole, respectively.10053
Clinical Experience as Extended Adjuvant Therapy
In a randomized trial involving 856 postmenopausal women with hormone receptor-positive early-stage breast cancer who remained free of disease after completing 5 years of adjuvant therapy with tamoxifen (47% of whom had also received the aromatase inhibitor aminoglutethimide for the first 2 years of therapy), those receiving 3 years of extended adjuvant therapy with anastrozole had reduced risk of disease recurrence and similar overall survival compared with those who received no further treatment.54 A separate randomized controlled trial compared 2 additional years of anastrozole therapy with 5 additional years of anastrozole therapy in 3208 postmenopausal women with hormone receptor-positive breast cancer who had completed 5 years of adjuvant endocrine therapy with tamoxifen, an aromatase inhibitor, or both sequentially.75 In this trial, disease-free survival was similar between groups, but the risk of clinical bone fracture was lower among patients who received 2 additional years of anastrozole therapy compared with the risk of bone fractures among patients who received 5 additional years of anastrozole therapy.75 The population enrolled in this trial represented patients at average risk for recurrence, so a disease-free survival benefit with 5 additional years of anastrozole therapy cannot be ruled out for patients at high risk for recurrence.75
The DATA trial examined the efficacy and safety of 3 versus 6 additional years of anastrozole adjuvant therapy in postmenopausal women with hormone receptor-positive early breast cancer who completed 2-3 years of tamoxifen adjuvant therapy without recurrence.81 At 5 years, the rates of disease-free survival were 83.1 and 79.4% in the 6-year and 3-year groups, respectively.81 Although disease-free survival rates were not significantly different between groups in the overall trial population, exploratory subgroup analyses suggested that 6 additional years of anastrozole therapy was associated with improved disease-free survival compared with 3 additional years of anastrozole therapy in patients with estrogen and progesterone receptor-positive expression having node-positive disease and larger tumor sizes.81 Arthralgia, myalgia, and osteopenia/osteoporosis were more common among patients who received 6 additional years of anastrozole therapy.81
In the 2010 American Society of Clinical Oncology (ASCO) guidelines on use of adjuvant endocrine therapy for hormone receptor-positive breast cancer, aromatase inhibitors were recommended either as initial therapy or as sequential therapy following 2-3 years of tamoxifen, for a total of 5 years of adjuvant endocrine therapy.10075 Choice of adjuvant endocrine therapy strategy should be based on individual adverse effect profiles of each agent, patient preferences, and pre-existing patient conditions.10075
Focused updates have been published by ASCO since 2010 with some revision to the recommendations for adjuvant endocrine therapy.10019 The updated document states that postmenopausal women with node-positive hormone receptor-positive breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2-3 years, then an aromatase inhibitor for 7-8 years.10019
Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, although benefits are likely narrower due to the lower risk for recurrence.10019 ASCO states that clinicians should consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen; during the course of adjuvant therapy, patients who are intolerant of one treatment may be switched to a different treatment.10075 Consult the ASCO guidelines for additional information.10019,10075
Adjuvant Therapy for Early-Stage Breast Cancer in Premenopausal Women
Endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) has been used in combination with ovarian suppression as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer.79,10010,10011,10012,10013,10023,10026
Efficacy and safety of endocrine therapy in combination with ovarian suppression as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer have been studied in several open-label, randomized, phase 3 studies.10010,10011,10013,10026
In the Suppression of Ovarian Function Trial (SOFT), 3066 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, tamoxifen 20 mg daily and ovarian suppression, or exemestane 25 mg daily and ovarian suppression.10010 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10010 Approximately one-half (53%) of patients enrolled in the study had received prior adjuvant chemotherapy.10010 The primary analysis involved comparison of tamoxifen and ovarian suppression with tamoxifen alone.10010 At a median follow-up of 8 years, disease-free survival and overall survival were prolonged, without a reduction in distant recurrences, in women receiving tamoxifen and ovarian suppression compared with those receiving tamoxifen alone; a disease-free survival benefit and a reduction in distant recurrences were observed, without an overall survival benefit, in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen alone.10012 (See Table 1.)
Treatment and Efficacy Measure | Hazard Ratio (vs tamoxifen) | Absolute Improvement (vs tamoxifen)a |
---|---|---|
Tamoxifen and Ovarian Suppression |
|
|
Disease-free survival | 0.76 | 4.2% |
Overall survival | 0.67 | 1.8% |
Freedom from distant recurrence | 0.86 | . . . |
Exemestane and Ovarian Suppression |
|
|
Disease-free survival | 0.65 | 7% |
Overall survival | 0.85 | . . . |
Freedom from distant recurrence | 0.73 | 2.8% |
aPercentage point difference in occurrence rates for the indicated treatment versus tamoxifen for events occurring at significantly different rates.
Subgroup analysis in the SOFT study suggested that the relative clinical benefits of the 3 treatments generally were similar regardless of prior use of adjuvant chemotherapy; however, no difference in disease-free survival was observed with the addition of ovarian suppression to tamoxifen therapy in patients at lower risk of breast cancer recurrence (i.e., older age, node-negative disease, low-grade tumor, smaller tumor size) who had not required prior adjuvant chemotherapy.10010,10012,10017 The absolute benefit of combined endocrine and ovarian suppression therapy was greater in higher-risk patients who had received adjuvant chemotherapy.10012 The absolute difference in 8-year disease-free survival rates between women receiving exemestane and ovarian suppression and those receiving tamoxifen alone was greater in women at higher risk of breast cancer recurrence (i.e., younger age, larger or high-grade tumor, lymph node involvement10010,10012 ) who had received prior adjuvant chemotherapy (9%) compared with those in the lower-risk cohort (5.2%).10012 The absolute difference in 8-year disease-free survival rates between women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone also was greater in women in the higher-risk cohort (5.3%) compared with those in the lower-risk cohort (3.2%).10012
A combined analysis of the SOFT study and the Tamoxifen and Exemestane Trial (TEXT) included data for 4690 premenopausal women with hormone receptor-positive operable breast cancer who were randomized to receive ovarian suppression and either exemestane 25 mg daily or tamoxifen 20 mg daily for 5 years.10011 Ovarian suppression could be achieved with triptorelin 3.75 mg administered by IM injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation.10011 In patients who received adjuvant chemotherapy in the TEXT study, triptorelin was initiated concomitantly with chemotherapy.10011 Approximately one-half (57.4%) of patients in the combined analysis received adjuvant chemotherapy.10011 A 5-year disease-free survival benefit and higher 5-year rates of freedom from breast cancer and freedom from distant recurrence were observed in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression.10011 Beneficial effects of combined exemestane and ovarian suppression therapy on disease-free survival and distant recurrences were maintained at 8 years.10012 (See Table 2.) Musculoskeletal symptoms (89.9 versus 77.8%) and osteoporosis (42.2 versus 27.9%) occurred more frequently in exemestane-treated patients compared with tamoxifen-treated patients.10012
Efficacy Measure | Exemestane and Ovarian Suppression (%) | Tamoxifen and Ovarian Suppression (%) |
---|---|---|
Disease-free survival, 5 years | 91.1 | 87.3 |
Overall survival, 5 years | 95.9 | 96.9 |
Freedom from breast cancer, 5 years | 92.8 | 88.8 |
Freedom from distant recurrence, 5 years | 93.8 | 92 |
Disease-free survival, 8 years | 86.8 | 82.8 |
Overall survival, 8 years | 93.4 | 93.3 |
Freedom from distant recurrence, 8 years | 91.8 | 89.7 |
In the HOBOE study, 1065 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with tamoxifen 20 mg daily, letrozole 2.5 mg daily, or letrozole 2.5 mg daily in combination with zoledronic acid 4 mg IV every 6 months; all patients received ovarian suppression with triptorelin 3.75 mg by IM injection every 4 weeks for 5 years or until the age of 55 years.10026 The majority (62.6%) of patients had received prior neoadjuvant or adjuvant chemotherapy.10026 At a median follow-up of approximately 5.3 years, a substantial disease-free survival benefit was observed in women receiving letrozole in combination with zoledronic acid and ovarian suppression (hazard ratio of 0.52, which corresponded to an absolute improvement in disease-free survival of 7.9%) but not in those receiving letrozole and ovarian suppression (hazard ratio of 0.72 with a 95% confidence interval of 0.48-1.07), compared with women receiving tamoxifen and ovarian suppression.10026 No difference in overall survival was observed among the 3 treatment groups.10026 However, at the time of the analysis, only 81% of the number of events required for final analysis had occurred.10026 Among patients receiving either letrozole or tamoxifen in combination with ovarian suppression, hypercholesterolemia (30.4 versus 20.3%), arthralgia (44.5 versus 22%), bone pain (29 versus 15.3%), insomnia (8.1 versus 4.2%), sensory neuropathy (13 versus 7.7%), and vaginal dryness ( 20.8 versus 11.7%) occurred more frequently in those receiving letrozole, while endometrial abnormalities (3 versus 6.8%) occurred more frequently in those receiving tamoxifen.10026
In the E-3193/INT-0142 study, 345 premenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive tamoxifen 20 mg daily with or without ovarian suppression for 5 years.10013 Ovarian suppression therapy could be achieved with goserelin 3.6 mg implanted subcutaneously every 4 weeks, leuprolide acetate 3.75 mg by IM injection every 4 weeks, bilateral oophorectomy, or bilateral ovarian irradiation.10013 Patients enrolled in the study had baseline characteristics associated with lower risk of breast cancer recurrence (i.e., node-negative disease, tumor size of 3 cm or less, no prior adjuvant chemotherapy, median age 45 years).10013,10017 At a median follow-up of approximately 9.9 years, results of this study were consistent with those of the SOFT study, demonstrating no difference in disease-free or overall survival between lower-risk women receiving tamoxifen and ovarian suppression and those receiving tamoxifen alone; however, interpretation of the results is limited by failure to meet the accrual goal of 1600 patients for superiority testing.10013,10017 In this study, the addition of ovarian suppression to tamoxifen therapy was associated with increased menopausal symptoms, decreased sexual function, increased breast cancer-specific symptoms, and lower quality of life during the first 3 years of therapy.10013
Use of adjuvant exemestane or tamoxifen therapy in combination with ovarian suppression improved disease-free survival rates compared with tamoxifen alone in premenopausal women with early-stage hormone receptor-positive breast cancer in the SOFT study;10012 however, more deaths occurred despite fewer distant recurrences in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression.10012,10016 Factors contributing to the discordance between distant recurrence rates and overall survival in women receiving exemestane and ovarian suppression have not been elucidated; however, some clinicians suggest that incomplete and/or intermittent estrogen suppression with gonadotropin-releasing hormone (GnRH) agonists used to achieve ovarian suppression may be a potential mechanism.10016,10025,10027 In the combined analysis of the SOFT and TEXT studies, clinical benefits (i.e., disease-free survival, freedom from distant recurrence) were observed in women receiving exemestane and ovarian suppression compared with those receiving tamoxifen and ovarian suppression;10012 however, in the HOBOE study, no difference in disease-free survival was observed between women receiving letrozole and ovarian suppression and those receiving tamoxifen and ovarian suppression.10026
The role of adding ovarian suppression to adjuvant endocrine therapy has not been fully elucidated; however, no discernible benefit from the addition of ovarian suppression to tamoxifen therapy has been observed in premenopausal women at lower risk of disease recurrence (i.e., older age, node-negative disease, low-grade tumor, smaller tumor size) in the SOFT and E-3193/INT-0142 studies, whereas a disease-free survival advantage was observed in a cohort of women at higher risk of disease recurrence (i.e., younger age, high-grade tumor, increased risk of lymph node involvement) receiving ovarian suppression in addition to exemestane or tamoxifen therapy in the SOFT study.10012,10017
Based on evidence from clinical trials,10010,10011,10012,10013,10023,10026 use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression as adjuvant therapy may be considered a reasonable choice (accepted) in premenopausal women with early-stage hormone receptor-positive breast cancer at higher risk of disease recurrence (i.e., younger age, larger or high-grade tumor, increased risk of lymph node involvement) and those who received prior adjuvant chemotherapy.10028 ASCO states that the duration of adjuvant GnRH agonist therapy should not exceed 5 years, since the toxicity of long-term (e.g., beyond 5 years) use of GnRH agonist-induced ovarian suppression has not been determined and comparative data for alternative treatment durations are lacking.10017,10019 Although inconsistent estrogen suppression may occur in premenopausal women receiving combined ovarian suppression and endocrine therapy, routine monitoring of serum estradiol concentrations is not recommended since there is insufficient evidence to support specific monitoring guidelines and validated estradiol assays are not widely available;10016,10017,10020,10025 however, ASCO recommends monitoring for physiologic changes that would suggest recovery of ovarian function.10017 ASCO states that clinicians should consider recurrence risk, adverse effects, patient preference, quality of life, consequences for childbearing, and the potential for ambiguity regarding the status of ovarian function (e.g., in women with chemotherapy-induced amenorrhea, hysterectomy-induced amenorrhea, incomplete ovarian suppression, or noncompliance with ovarian suppression therapy) when considering the addition of ovarian suppression therapy to adjuvant endocrine therapy.10017,10019
Advanced Breast Cancer in Postmenopausal Women
Anastrozole is used for the first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women.1 Anastrozole is also used for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy.1
Clinical Experience as Initial Therapy
Data from 2 double-blind, randomized clinical trials indicate that anastrozole is at least as effective as tamoxifen for producing objective tumor response and delaying tumor progression in such patients.21,22 In the 2 studies, a total of 1021 postmenopausal patients (age range: 30-92 years) were randomized to receive anastrozole 1 mg once daily or tamoxifen 20 mg once daily for hormone receptor-positive (i.e., estrogen receptor-positive, progesterone receptor-positive, or both) breast tumors or hormone receptor-unknown breast tumors.1
Results from trial 0030, a North American study involving 353 patients (about 90% with hormone receptor-positive breast tumors and 10% with hormone receptor-unknown breast tumors), showed a similar objective response rate (about 21 and 17%, respectively) and an increased median time to progression (11.1 versus 5.6 months, respectively) for patients receiving anastrozole compared with those receiving tamoxifen at a median follow-up of about 18 months.1,22 In trial 0027, a predominantly European study involving 668 patients (about 45% with hormone receptor-positive breast tumors and 55% with hormone receptor-unknown breast tumors), a similar objective response rate (about 33% in both groups) and median time to progression (about 8 months in both groups) were reported at a median follow-up of 19 months in patients receiving anastrozole or tamoxifen.1,21
Conclusions concerning differences in overall survival between the 2 treatments could not be made because of the low number of deaths occurring across treatment groups in either study at the time of data analysis.1,21,22 A later analysis of combined patient data for the 2 studies at a median of 43.7 months of follow-up showed no difference in survival between the treatment groups (death rate: 56%);55 analysis of pooled data56 from published studies for first-line, second-line, or subsequent therapy of advanced breast cancer that included these 2 studies55 suggests that treatment with third-generation aromatase inhibitors, such as anastrozole, as first-line therapy for advanced breast cancer offers a small survival advantage (about 11%) compared with standard hormonal therapy, such as tamoxifen. Analysis of combined data for the 2 studies shows that adverse effects occurred at a similar frequency in patients receiving anastrozole or tamoxifen.1,40,55
The FALCON randomized controlled trial compared intramuscular fulvestrant to anastrozole 1 mg orally daily for the treatment of advanced hormone receptor-positive breast cancer in postmenopausal patients with no history of prior endocrine therapy.76 In this trial, fulvestrant was associated with longer progression-free survival than anastrozole (median 16.6 months, compared to 13.8 months in the anastrozole group).76 Overall survival data were not yet mature.76
Clinical Experience as Second-Line Therapy After Tamoxifen
Data from 2 comparative clinical trials concluded that no significant differences exist between anastrozole and megestrol acetate in postmenopausal women with advanced breast cancer who have had disease progression following tamoxifen therapy for either advanced or early breast cancer.1,2,8
In these clinical trials, a total of 764 postmenopausal women with advanced breast cancer that progressed following tamoxifen therapy (for either advanced or early breast cancer) were randomized to receive anastrozole 1 mg or 10 mg daily, or megestrol acetate 40 mg 4 times daily.1,23 Most of the patients enrolled had estrogen receptor-positive tumors; patients with estrogen receptor-negative disease were eligible only if they previously had responded to tamoxifen (5-6% of the patients in each trial).1,23 Some patients also had received previous cytotoxic therapy.1 The primary efficacy variables were time to progression and objective response rate, and similar results were observed among treatment groups and between the 2 trials.1
In trial 0004, a North American study involving 386 patients (81% with hormone receptor-positive breast tumors), a median time to progression of 5.7, 5.3, and 5.1 months, respectively, and an objective response rate of 12.5, 10, and 10.2%, respectively, were reported in patients receiving anastrozole 1 mg daily, anastrozole 10 mg daily, and megestrol acetate 40 mg 4 times daily.1 In trial 0005, a predominantly European study involving 378 patients (58% with hormone receptor-positive breast tumors), a median time to progression of 4.4, 5.3, and 3.9 months, respectively, and an objective response rate of 12.6, 15.3, and 14.4%, respectively, were reported in patients receiving anastrozole 1 mg daily, anastrozole 10 mg daily, and megestrol acetate 40 mg 4 times daily.1
Pooled analysis of data from the 2 trials showed a median time to progression of 4.8, 5.3, and 4.6 months, respectively, and an objective response rate of 12.5, 12.5, and 12.3%, respectively, in patients receiving anastrozole 1 mg daily, anastrozole 10 mg daily, and megestrol acetate 40 mg 4 times daily.1,23 Similar efficacy was observed for patients receiving anastrozole 1 mg and megestrol acetate, and there was no evidence of superior efficacy of the 10-mg daily dose of anastrozole compared with the 1-mg daily dose.1,23 Analysis of pooled data56 from published studies for first-line, second-line, or subsequent therapy of advanced breast cancer that included these 2 studies23 suggests that treatment with third-generation aromatase inhibitors, such as anastrozole, as second-line or subsequent therapy for advanced breast cancer offers a small survival advantage (about 14%) compared with standard hormonal therapy, such as megestrol acetate.23 Weight gain was reported less frequently with anastrozole (1 mg daily) than with megestrol acetate (40 mg 4 times daily) in these clinical trials.1,2,8
One open-label randomized controlled trial compared anastrozole to letrozole for the treatment of postmenopausal women with advanced breast cancer whose disease had progressed following treatment with tamoxifen or another antiestrogen treatment.84 In this trial, the overall response rate was higher in the letrozole group (19.1 versus 12.3% with anastrozole), but no significant differences in time to progression, clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure, or overall survival were observed between groups.84 Two additional randomized controlled trials have compared anastrozole to fulvestrant for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following prior endocrine therapy; these trials did not find significant differences in efficacy between treatments.82,83
Updated guidelines from ASCO provide recommendations for treatment of women and men with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.4000 According to ASCO, combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a cyclin-dependent kinase (CDK) 4/6 inhibitor should be offered first line to postmenopausal patients with treatment-naive hormone receptor-positive metastatic breast cancer.4000 Although most postmenopausal patients appear to benefit from combination therapy, endocrine monotherapy with an aromatase inhibitor may be the best choice for first-line therapy in some patients; the choice between monotherapy and combination therapy should be based on factors such as disease burden, disease-free interval, patient age, patient choice, and treatment tolerance.4000
Choice of second-line hormonal therapy should take into account prior treatment exposure and response to previous endocrine therapy; options for second-line therapy include tamoxifen, an aromatase inhibitor, or fulvestrant with or without everolimus.4000 Patients with progressive disease during treatment with aromatase inhibitors and patients who develop recurrence within 1 year of adjuvant aromatase inhibitor therapy should be offered fulvestrant and a CDK4/6 inhibitor.4000 Treatment with exemestane and everolimus may be offered, either before or after treatment with fulvestrant, to postmenopausal patients with hormone receptor-positive metastatic disease that progressed during treatment with a nonsteroidal aromatase inhibitor; this combination should not be offered as first-line therapy for patients who relapse more than 12 months from prior nonsteroidal aromatase inhibitor therapy or for those who are naive to hormonal therapy.4000 Consult the ASCO guideline for additional information.4000
Advanced Breast Cancer in Premenopausal Women
For premenopausal women with treatment-naive, hormone receptor-positive metastatic breast cancer, ASCO recommends combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a CDK 4/6 inhibitor, in conjunction with chemical ovarian function suppression.4000 In most patients, these combination regimens are the preferred first-line treatment, based on data demonstrating improvements in progression-free and overall survival.4000 Ovarian suppression (e.g., with goserelin) or ablation in combination with hormonal therapy should be offered to premenopausal women with metastatic hormone receptor-positive breast cancer; patients without prior exposure to hormonal therapy may be treated with tamoxifen or ovarian suppression/ablation alone, but combination therapy is preferred.4000
Reduction in the Incidence of Breast Cancer in Women at High Risk
Aromatase inhibitors, such as anastrozole, have been used for reduction in the incidence of breast cancer among women who are at high risk for developing the disease.77,80,10050,10055
The IBIS-II trial was a randomized controlled trial enrolling postmenopausal women with an increased risk of breast cancer; women were eligible for enrollment if they were 40-44 years of age with a risk of breast cancer 4 times higher than that of the general population, 45-60 years of age with a risk of breast cancer twice that of the general population, or 60-70 years of age with a risk of breast cancer 1.5 times higher than that of the general population.77 Women were also eligible for enrollment if they did not meet these criteria but had a 10-year risk of breast cancer greater than 5% according to the Tyrer-Cuzick model.77 Patients were randomized to receive anastrozole 1 mg daily or matching placebo for 5 years.77 After a median follow-up of 5 years, rates of breast cancer were 2 and 4% in the anastrozole and placebo groups, respectively.77 The predicted cumulative incidence of breast cancer after 7 years was doubled with placebo compared to anastrozole.77 At a median follow-up time of 131 months, 5 years of anastrozole treatment was associated with a 49% reduction in the risk for breast cancer compared to placebo.80
Updated guidelines from ASCO provide recommendations for use of endocrine therapy for breast cancer risk reduction in postmenopausal women not previously diagnosed.10050 According to ASCO, anastrozole is an alternative to exemestane, tamoxifen, or raloxifene in postmenopausal women (35 years of age or older) to reduce the risk of hormone receptor-positive invasive breast cancer.10050 Anastrozole should not be used in premenopausal women for breast cancer risk reduction.10050 Consult the ASCO guideline for additional information.10050
The US Preventative Services Task Force Evidence Report summarized the evidence of efficacy and harm of medications used as primary prevention of breast cancer, including tamoxifen, raloxifene, and the aromatase inhibitors anastrozole and exemestane.10055 In placebo-controlled trials, all of these agents showed efficacy in reducing invasive breast cancer.10055 Risk of thromboembolic events was higher with tamoxifen and raloxifene versus placebo.10055 Risk of endometrial cancer was also higher with tamoxifen compared with placebo.10055 The authors of the report noted that research is lacking for optimal doses, duration of use, persistence of effects after treatment for most medications, and outcomes in women who are nonwhite, premenopausal, have comorbidites, or are taking additional medications for other indications.10055
Anastrozole is administered orally.1
Food does not affect the absorption of anastrozole, and the drug may be administered without regard to meals.1
Commercially available anastrozole tablets should be stored at a controlled room temperature of 20-25°C.1
Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer
For adjuvant therapy in the treatment of early-stage, hormone receptor-positive breast cancer in postmenopausal women, the recommended dosage of anastrozole is 1 mg daily.1
The optimal duration of therapy is unknown.1 In a large, randomized clinical trial (the ATAC trial), the duration of anastrozole therapy was 5 years.1 The American Society of Clinical Oncology (ASCO) states that postmenopausal women with node-positive hormone receptor-positive early breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2-3 years, then an aromatase inhibitor for 7-8 years.10019 Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, although benefits are likely narrower due to the lower risk for recurrence.10019
Adjuvant Therapy for Early-stage Breast Cancer in Premenopausal Women in Combination with Ovarian Suppression
When used in combination with ovarian suppression as adjuvant therapy in premenopausal women with early-stage hormone receptor-positive breast cancer, anastrozole has been administered at a dosage of 1 mg once daily.79,10023
Advanced Breast Cancer in Postmenopausal Women
For the first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women, the recommended dosage of anastrozole is 1 mg daily.1 Anastrozole therapy should be continued until tumor progression is evident.1
For the second-line treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy, the recommended dosage of anastrozole is 1 mg daily.1 Anastrozole therapy should be continued until tumor progression is evident.1
Reduction in the Incidence of Breast Cancer in Women at High Risk
For reduction in the incidence of breast cancer among women who are at high risk for developing the disease, anastrozole has been administered at a dosage of 1 mg once daily for 5 years.77,10050
The manufacturer states that no dosage adjustment is required in patients with mild to moderate hepatic impairment or stable hepatic cirrhosis.1 Anastrozole has not been studied in patients with severe hepatic impairment.1
Reduction in renal clearance does not affect total body clearance of anastrozole since only about 10% of the drug is excreted unchanged in urine.1 Therefore, adjustment of anastrozole dosage is not required in patients with renal impairment.1
Because no evidence of altered pharmacokinetics has been observed in women older than 80 years of age compared with women younger than 50 years of age, the manufacturer states that adjustment of anastrozole dosage is not necessary in geriatric patients.1
Ischemic Cardiovascular Events
Among patients receiving adjuvant therapy in clinical trials, ischemic cardiovascular events were reported in similar proportions of patients receiving anastrozole or tamoxifen (4 versus 3%).1 Angina pectoris or myocardial infarction was reported in 2.3 or 1.2%, respectively, of those receiving adjuvant therapy with anastrozole compared with 1.6 or 1.1%, respectively, of those receiving tamoxifen.1 In the subset of patients with preexisting ischemic heart disease, ischemic cardiovascular events were reported in 17% of patients receiving anastrozole compared with 10% of those receiving tamoxifen; angina pectoris or myocardial infarction was reported in 11.6 or 0.9%, respectively of those receiving anastrozole compared with 5.2 or 3.2%, respectively, of those receiving tamoxifen.1
Consider risks and benefits of anastrozole therapy in patients with pre-existing ischemic heart disease.1
Because anastrozole lowers circulating estrogen concentrations, it may cause a reduction in bone mineral density (BMD).1,43,48 Analysis of data at 12 and 24 months from a substudy of the ATAC trial showed that whereas mean values for lumbar spine and total hip BMD (compared with baseline) decreased in patients receiving anastrozole, these values increased in those receiving tamoxifen.1,43,48 For patients receiving adjuvant therapy with anastrozole, the rate of bone loss at the lumbar spine slowed at 2-5 years compared with the change measured from baseline to 2 years, but the rate of bone loss at the hip did not slow over the 5-year period.43 Analysis of the data at 5 years indicated accelerated bone loss at the lumbar spine and the hip in patients receiving anastrozole, compared with a slight increase in BMD in the lumbar spine but not in the hip in patients receiving tamoxifen.43 Among women who had normal BMD at baseline, none developed osteoporosis after 5 years of anastrozole therapy, but osteopenia was more frequent in these patients than in those receiving tamoxifen (17 versus 3%).43
Analysis of data from the ATAC study at a median follow-up of 10 years (median adjuvant treatment duration of 5 years) showed that the cumulative incidence of all first fractures (both serious and nonserious, occurring either during or after treatment) was higher in the anastrozole group compared with the tamoxifen group (15 versus 11%).1 Fractures were reported more frequently during treatment in patients receiving anastrozole compared with those receiving tamoxifen; however, after completion of treatment, the incidence of fractures was similar between groups.1,66
Consider BMD monitoring in patients receiving anastrozole.1
Among patients receiving adjuvant therapy in the ATAC trial, increased serum cholesterol concentrations were reported more frequently in patients receiving anastrozole compared with those receiving tamoxifen (9 versus 3.5%).1 However, in another clinical trial, no clinically important changes in concentrations of total, high-density lipoprotein (HDL)-, or low-density lipoprotein (LDL)-cholesterol or concentrations of triglycerides were observed from baseline to 12 months in patients receiving anastrozole alone or in conjunction with risedronate.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and findings from animal studies, anastrozole may cause fetal harm when administered during pregnancy.1 Embryofetal toxicity has been reported in rats at 9 times the human clinical exposure, and pregnancy failure has been reported in rabbits at 16 times the recommended human dose.1
Advise pregnant patients and females of reproductive potential of the potential risk to a fetus.1 Perform pregnancy testing in females of reproductive potential prior to starting anastrozole.1 Advise females of reproductive potential to use effective contraception during anastrozole treatment and for at least 3 weeks after the last dose.1
Anastrozole may cause fetal harm; the drug has been shown to be embryotoxic, fetotoxic, and abortifacient in animals.1 The manufacturer states that a pregnancy test should be performed prior to initiation of anastrozole therapy in females of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of therapy.1 If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus and the potential risk for loss of the pregnancy.1
Adequate, well-controlled studies of anastrozole in pregnant women have not been conducted.1 Anastrozole has been shown to cross the placenta in rats and rabbits receiving oral doses of 0.1 mg/kg (approximately 1 and 1.9 times the recommended human dose, respectively, on a mg/m2 basis).1 Increased pregnancy loss (increased preimplantation and/or postimplantation loss, increased resorption, and decreased numbers of live fetuses) was demonstrated in rats and rabbits receiving anastrozole dosages equal to or exceeding 0.1 and 0.02 mg/kg daily, respectively (about one and one-third times the recommended human dosage, respectively, on a mg/m2 basis), during the period of organogenesis; in rats, this effect was dose-related.1 In rats receiving dosages equal to or exceeding 0.1 mg/kg daily, placental weights were increased.1
In rats, anastrozole dosages of 1 mg/kg daily (which produced steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 19 and 9 times higher, respectively, than those observed in healthy postmenopausal women receiving the recommended dose) resulted in fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights).1 In rats, no evidence of teratogenicity was observed at dosages of up to 1 mg/kg daily.1 In rabbits, anastrozole dosages equal to or exceeding 1 mg/kg daily (about 16 times the recommended human dosage on a mg/m2 basis) caused pregnancy failure.1 No evidence of teratogenicity was observed in rabbits receiving anastrozole 0.2 mg/kg daily (about 3 times the recommended human dosage on a mg/m2 basis).1
It is not known whether anastrozole or its metabolites are distributed into human milk or if the drug has any effect on nursing infants or on milk production.1 Because many drugs are distributed into milk and because tumorigenic effects of anastrozole have been observed in animals and anastrozole has the potential to cause serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during anastrozole therapy and for 2 weeks after discontinuance of the drug.1
Females of Reproductive Potential
Anastrozole may cause fetal harm; the drug has been shown to be embryotoxic, fetotoxic, and abortifacient in animals.1 The manufacturer states that a pregnancy test should be performed prior to initiation of anastrozole therapy in females of reproductive potential and that such patients should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of therapy.1
Impairment of fertility and effects on the reproductive organs associated with anastrozole have been demonstrated in animal studies.1 In female rats, oral administration of anastrozole at a dosage of 1 mg/kg daily (about 10 times the recommended human dosage on a mg/m2 basis and resulting in an AUC0-24h about 9 times higher than that observed in postmenopausal women receiving the recommended dose) from 2 weeks before mating to pregnancy day 7 caused a high incidence of infertility and reduced numbers of viable pregnancies.1 Preimplantation loss of ova or fetus was increased at dosages equal to or exceeding 0.02 mg/kg daily (about one-fifth the recommended human dosage on a mg/m2 basis).1 Recovery of fertility was observed following a 5-week nondosing period that followed 3 weeks of dosing.1 Whether the effects observed in rats are indicative of impaired fertility in humans receiving anastrozole is not known.1
In multiple-dose studies in rats, anastrozole dosages equal to or exceeding 1 mg/kg daily for 6 months (which resulted in steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 19 and 9 times higher, respectively, than those observed in healthy postmenopausal humans receiving the recommended dosage) resulted in hypertrophy of the ovaries and development of follicular cysts.1 In multiple-dose studies in dogs receiving anastrozole dosages equal to or exceeding 1 mg/kg daily for 6 months (which produced steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 22 and 16 times higher, respectively, than those observed in postmenopausal women receiving the recommended dosage), hyperplastic uteri were observed.1 The relationship between the reproductive effects observed in animals and possible effects of the drug on fertility in humans is not known.1
Efficacy of anastrozole for the treatment of pubertal gynecomastia in adolescent males and for the treatment of progressive precocious puberty associated with McCune-Albright syndrome in girls has not been established.1
Results of a randomized, double-blind, placebo-controlled trial in 80 adolescent males 11-18 years of age with pubertal gynecomastia failed to establish efficacy of anastrozole (1 mg daily for 6 months) in reducing gynecomastia or relieving breast pain.1 Serum estradiol concentrations were reduced by 15.4 or 4.5% in patients receiving anastrozole or placebo, respectively.1 Patients receiving anastrozole were more likely to experience treatment-related adverse effects (16.3 versus 8.1%), and the difference was related mainly to higher rates of acne and headache in those receiving anastrozole.1 One patient discontinued anastrozole therapy because of testicular enlargement.1
Results of a noncomparative open-label trial of anastrozole (1 mg daily for 12 months) in 28 girls (2 to less than 10 years of age) with McCune-Albright syndrome and progressive precocious puberty showed no reduction from baseline in the frequency of vaginal bleeding days or in the rate of increase in bone age and no clinically important changes in Tanner staging, mean ovarian or uterine volume, or mean predicted adult height.1 A small reduction in growth rate was observed; however, because the study was uncontrolled, it is unclear whether this effect was related to anastrozole or to other confounding factors (e.g., variations in endogenous estrogen levels commonly observed in patients with McCune-Albright syndrome).1 Adverse effects (i.e., nausea, acne, extremity pain, increased aminotransferase concentrations, allergic dermatitis) were reported in 18% of patients.1
Pharmacokinetics of anastrozole were similar in adolescent males with pubertal gynecomastia and in girls with McCune-Albright syndrome, and the elimination half-life in these pediatric populations (about 47 hours) was similar to that observed in postmenopausal women with breast cancer.1
Among patients receiving anastrozole as adjuvant therapy for early-stage breast cancer in the ATAC trial, 45% were 65 years of age or older.1 Subgroup analysis showed that anastrozole did not provide the same benefit for disease-free survival in women 65 years of age or older (hazard ratio of 0.93 with a 95% confidence interval of 0.8-1.08) that it provided in postmenopausal women younger than 65 years of age (hazard ratio of 0.79 with a 95% confidence interval of 0.67-0.94).1
Among patients receiving anastrozole as first-line or second-line therapy in clinical trials, about 50% were 65 years of age or older.1 No difference in efficacy was observed for geriatric patients (65 years or older) compared with younger patients receiving anastrozole as second-line therapy for advanced breast cancer; moderately greater efficacy was observed for geriatric patients (65 years or older) receiving either anastrozole or tamoxifen as first-line therapy for advanced breast cancer.1
The apparent oral clearance of anastrozole was reduced by approximately 30% in individuals with stable hepatic cirrhosis related to alcohol abuse compared with controls with normal hepatic function.1 However, plasma anastrozole concentrations observed in individuals with hepatic cirrhosis were within the range of concentrations observed in normal individuals across all clinical trials.1
The manufacturer states that no dosage adjustment is required in patients with mild to moderate hepatic impairment or stable hepatic cirrhosis.1 Anastrozole has not been studied in patients with severe hepatic impairment.1
Although the renal clearance of anastrozole decreases proportionally with creatinine clearance and is reduced by about 50% in individuals with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m2) compared with controls, total body clearance of anastrozole is reduced by only 10% in patients with severe renal impairment.1
Adjustment of anastrozole dosage is not required in patients with renal impairment.1
In the early breast cancer study (ATAC), the most common adverse effects (occurring in 10% or more of patients) included hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea, vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, and lymphedema.1
In advanced breast cancer studies, the most common adverse effects (occurring in 10% or more of patients) included hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and peripheral edema.1
Anastrozole has been shown to inhibit in vitro metabolic reactions catalyzed by cytochrome P-450 (CYP) isoenzymes 1A2, 2C8/9, and 3A4, but only at relatively high concentrations.1 It is considered unlikely that anastrozole, when administered at the recommended dosage, will result in clinically important interactions with drugs metabolized by CYP enzymes.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Anastrozole did not alter systemic exposure (as measured by peak plasma concentrations and area under the concentration-time curve [AUC]) or anticoagulant effects of either R - or S -warfarin.1 It is considered unlikely that anastrozole, when administered at the recommended dosage, will result in clinically important interactions with drugs metabolized by CYP enzymes.1 Anastrozole did not inhibit CYP isoenzyme 2A6 or 2D6 in human liver microsomes, and the drug did not alter the pharmacokinetics of antipyrine.1
Because estrogens may diminish the pharmacologic action of anastrozole, the drugs should not be used concomitantly.1
Data from a subprotocol of the ATAC trial indicate that concomitant use of anastrozole and tamoxifen does not affect the pharmacokinetics of tamoxifen or N -desmethyltamoxifen, its principal active metabolite.1,26 The mean plasma anastrozole concentration was reduced by an average of 27% in patients receiving tamoxifen and anastrozole versus anastrozole alone, but analysis of blood samples from a different subprotocol of the ATAC trial demonstrates similar degrees of suppression of plasma estradiol concentrations for anastrozole alone and in combination with tamoxifen.26 Although the clinical importance of this pharmacokinetic interaction is uncertain,26 combination therapy did not demonstrate greater efficacy than use of tamoxifen alone, and the concomitant use of anastrozole and tamoxifen is not recommended.1
Anastrozole, a benzyltriazole derivative, is a selective, nonsteroidal aromatase inhibitor.1,6 Competitive aromatase inhibitors, such as anastrozole, also have been referred to as type II inhibitors of the enzyme.16 Anastrozole differs structurally from aminoglutethimide but shares the pharmacologic activity of competitive aromatase inhibition; although both drugs are selective nonsteroidal inhibitors, anastrozole is more potent and selective on a molar basis.14,17 Anastrozole is a triazole derivative; the N-4 nitrogen of the triazole ring, which coordinates with the heme iron atom of the aromatase enzyme complex, is thought to be responsible for the high affinity of the drug for the estrogen synthetase enzyme.14
Anastrozole selectively inhibits the conversion of androgens to estrogens.1,6,14 In postmenopausal women, ovarian secretion of estrogen declines and conversion of adrenal androgens (mainly androstenedione and testosterone) to estrone and estradiol in peripheral tissues (adipose, muscle, and liver), catalyzed by the aromatase enzyme, is the principal source of estrogens.1,14,17 Anastrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P-450 unit of the enzyme; suppression of estrogen biosynthesis in all tissues reduces serum concentrations of circulating estrogens, including estrone, estradiol, and estrone sulfate.14,17 Because estrogen acts as a growth factor for hormone-dependent breast cancer cells, anastrozole-induced reduction of serum and tumor concentrations of estrogen inhibits tumor growth and delays disease progression.1,14,16
Anastrozole selectively inhibits synthesis of estrogens and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.1,6,14 In animals, anastrozole has not been shown to possess direct progestogenic, androgenic, or estrogenic activity, but alterations in the circulating concentrations of progesterone, androgens, and estrogens have been observed.1
The effect of anastrozole on serum estradiol concentrations in premenopausal women has not been studied.1,48 Ovarian secretion is the principal source of estrogen in premenopausal women; because it acts by suppressing other sources of estrogens, anastrozole would not be expected to lower serum estradiol concentrations in women with functioning ovaries.1,48
The pharmacokinetics of anastrozole are linear over the dose range of 1-20 mg and are not altered with repeated dosing.1 The pharmacokinetic disposition of anastrozole is similar in female patients with breast cancer and in healthy postmenopausal women.1 Anastrozole is rapidly and well absorbed into systemic circulation following oral administration; peak plasma concentrations generally are attained within 2 hours when the drug is administered in the fasted state.1 Plasma concentrations approach steady state after about 7 days of once-daily dosing, and steady-state concentrations are approximately 3-4 times higher than concentrations achieved after a single dose of the drug.1 Food reduces the rate but does not affect the extent of oral absorption of anastrozole.1 When anastrozole was administered 30 minutes after food, the mean peak plasma concentration of the drug was decreased by 16% and the median time to peak plasma concentration was delayed by 3 hours.1
Within the therapeutic plasma concentration range, anastrozole is 40% bound to plasma proteins.1 A mean terminal elimination half-life of approximately 50 hours has been reported.1 Anastrozole is extensively metabolized in the liver.1 Hepatic metabolism accounts for about 85% of the elimination of anastrozole, with renal excretion accounting for only about 10% of total clearance.1 Studies with radiolabeled drug have shown that about 85% of an orally administered dose is recovered in urine and feces.1 Metabolism of anastrozole occurs via N -dealkylation, hydroxylation, and glucuronidation.1 Three metabolites of anastrozole have been identified in human plasma and urine: triazole, a glucuronide conjugate of anastrozole, and a glucuronide conjugate of hydroxyanastrozole.1 Triazole, the major circulating metabolite of anastrozole, lacks pharmacologic activity, and the aromatase-inhibiting activity of anastrozole results principally from the parent drug.1
Among healthy postmenopausal women and female patients with breast cancer, no age-related differences in pharmacokinetics of anastrozole have been observed in women older than 80 years of age compared with women younger than 50 years of age.1
Steady-state minimum plasma concentrations averaged 25.7 and 30.4 ng/mL, respectively, in white and Japanese postmenopausal women receiving anastrozole 1 mg daily for 16 days; serum estradiol and estrone sulfate concentrations were similar between the groups.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets, film-coated | 1 mg* | Anastrozole Film-coated Tablets | |
ANI |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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10002. Goss PE, Ingle JN, Pritchard KI et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013; 31:1398-404. [PubMed 23358971][PubMedCentral]
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