VA Class:AN900
Exemestane, an aromatase inhibitor, is an antineoplastic agent.1, 2, 3, 4, 5, 6
Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer
Exemestane is used as sequential adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer who have received 2-3 years of adjuvant tamoxifen therapy and are switched to exemestane to complete a total of 5 consecutive years of adjuvant hormonal therapy.1, 8, 9, 11 Data from two phase 3 randomized open-label clinical trials indicate that initial therapy† with exemestane is at least as effective as initial therapy with anastrozole or sequential therapy with tamoxifen followed by exemestane in postmenopausal women with early-stage hormone receptor-positive breast cancer.10001, 10002 Exemestane has also been used as extended adjuvant therapy† in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy.10005
Clinical Experience as Sequential Adjuvant Therapy
In Intergroup Exemestane Study 031, a randomized, double-blind trial, 4724 postmenopausal women who previously had been diagnosed with early-stage breast cancer and who remained free of disease after 2-3 years of adjuvant tamoxifen therapy were randomized to switch to exemestane therapy or to continue receiving tamoxifen to complete a total of 5 years of adjuvant hormonal therapy.1, 8, 9, 11 The median duration of tamoxifen therapy prior to randomization was approximately 28 months.1 Exemestane was administered at a dosage of 25 mg daily, and tamoxifen was administered at a dosage of 20 or 30 mg daily (about 3% of patients received the 30-mg dosage).1, 8, 9, 11 About 86% of patients enrolled in the study had hormone receptor-positive disease.1, 9, 11 The primary end point of the trial was disease-free survival.1, 8, 9, 11
Analysis of the data at a median follow-up of 34.5 months, when patients had received study treatment for a median of 27 months, showed that disease-free survival was prolonged in patients who were switched from tamoxifen to exemestane compared with those who continued receiving tamoxifen (hazard ratio of 0.69).1 Distant recurrence-free survival and time to contralateral breast cancer also were prolonged in patients receiving exemestane.1 Breast cancer-related events in patients receiving exemestane versus tamoxifen included locoregional recurrence (1.4 versus 1.9%), distant recurrence (5.4 versus 7.7%), primary cancer in the contralateral breast (0.3 versus 1%), breast cancer-related death (0.04 versus 0.25%), and ipsilateral breast cancer (0.04 versus 0%).1 No difference in overall survival was observed between the 2 treatment groups overall or within the subset of patients with hormone receptor-positive disease.1
Subsequent analyses showed that the disease-free survival benefit associated with switching to exemestane was maintained.9, 11, 10054 At a median follow-up of about 4.6 years a hazard ratio of 0.76 was reported, which corresponded to an absolute improvement in disease-free survival of 3.3 or 3.4% at 2.5 or 5 years, respectively, after randomization.9 At a median follow-up of about 7.6 years, a hazard ratio of 0.84 was reported, which corresponded to an absolute difference in disease-free survival of 2.8 or 4.1% at 5 or 8 years, respectively, after randomization.11 At a median of 120 months, a reduction in breast cancer-related events was seen, with an absolute difference of 4% between the 2 groups and a hazard ratio of 0.81 in favor of switching to exemestane.10054 Among patients with hormone receptor-positive/unknown disease, use of exemestane as sequential adjuvant therapy was associated with a modest overall survival benefit (2.1%, hazard ratio of 0.89).10054
Clinical Experience as Initial Adjuvant Therapy
Data from two phase 3, randomized, open-label clinical trials indicate that initial therapy† with exemestane is at least as effective as initial therapy with anastrozole or sequential therapy with tamoxifen followed by exemestane in postmenopausal women with early-stage hormone receptor-positive breast cancer.10001, 10002
In the first study (Tamoxifen Exemestane Adjuvant Multinational [TEAM]), 9779 postmenopausal women with early-stage hormone receptor-positive breast cancer were randomized to receive exemestane 25 mg daily for 5 years or sequential therapy with tamoxifen 20 mg daily for 2-3 years followed by exemestane 25 mg daily for a total treatment duration of 5 years.10001 Most (98%) of the patients enrolled in the study had estrogen receptor-positive tumors.10001 The primary end point of the study was disease-free survival.10001 At a median follow-up of 5.1 years, no significant difference in estimated 5-year disease-free survival was observed between patients receiving sequential therapy and those receiving initial exemestane therapy (85 and 86%, respectively; hazard ratio of 0.97 with a 95% confidence interval of 0.88-1.08); in addition, no difference in 5-year overall survival was observed between the groups.10001 Disease relapse or breast cancer-related death occurred in similar proportions of patients receiving sequential therapy (11%) or initial exemestane therapy (10%).10001 In this study, fractures, osteoporosis, hyperlipidemia, hypertension, and cardiac failure occurred more frequently in patients receiving initial exemestane therapy, whereas venous thrombosis, vaginal bleeding, and endometrial disorders occurred more frequently in those receiving sequential therapy.10001
Risk of breast cancer recurrence for patients in the TEAM trial was also evaluated at 10 years.10056 A total of 6120 patients were included in the long-term follow-up; 3045 patients given sequential therapy and 3075 given exemestane.10056 The primary outcome assessed was disease-free survival.10056 At the 10-year follow-up (median 9.8 years), disease-free survival was 67% for exemestane and 67% for sequential therapy (hazard ratio, 0.96).10056
In the second study (MA.27), 7576 postmenopausal women with hormone receptor-positive primary invasive breast cancer were randomized to receive exemestane 25 mg daily or anastrozole 1 mg daily for 5 years, with or without celecoxib; however, random assignment to celecoxib was halted when data from another study suggested that celecoxib may increase cardiovascular risk.10002 Patients were stratified according to lymph node status, receipt of prior adjuvant chemotherapy, use of concomitant trastuzumab therapy, and previous random assignment to celecoxib and concomitant prophylactic aspirin therapy.10002 Most (99%) of the patients enrolled in the study had estrogen receptor-positive tumors.10002 The primary end point of the study was event-free survival.10002 At a median follow-up of 4.1 years, no significant difference in estimated 4-year event-free survival was observed between patients receiving exemestane and those receiving anastrozole (91 and 91.2%, respectively; hazard ratio of 1.02 with a 95% confidence interval of 0.87-1.18).10002 In addition, no difference in overall survival was observed between the groups.10002 Elevations in aminotransferase (ALT or AST) concentrations (3 versus 1%), elevations in serum bilirubin concentrations (2 versus 1%), and atrial fibrillation (2 versus 1%) occurred more frequently in patients receiving exemestane, whereas hyperlipidemia (18 versus 15%), hypertriglyceridemia (3 versus 2%), and osteoporosis (35 versus 31%) occurred more frequently in patients receiving anastrozole.10002
Sequential Versus Initial Adjuvant Therapy
The efficacy of exemestane 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
Efficacy of exemestane as extended adjuvant therapy in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy has been evaluated in a double-blind, placebo-controlled, randomized phase 3 trial (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-33) in postmenopausal women mostly with hormone receptor-positive breast cancer (97% hormone receptor-positive, 3% hormone receptor-unknown).10005 In this trial, 1598 patients who had received adjuvant therapy with tamoxifen for approximately 5 years (range: approximately 4.75-5.6 years) were randomized to receive exemestane 25 mg daily or placebo for 5 years.10005 Based on interim results from a similarly designed trial demonstrating benefit from extended adjuvant therapy with letrozole, recruitment of patients for the NSABP B-33 trial was halted early, the study was unblinded, and exemestane therapy was offered to all women who had been receiving placebo.10005 After the study was unblinded, 44% of patients randomized to receive placebo crossed over to receive exemestane therapy and 72% of patients randomized to receive exemestane continued their assigned therapy.10005
At a median follow-up of 30 months, the estimated 4-year disease-free survival did not differ significantly between patients receiving exemestane and those receiving placebo (91 versus 89%, respectively, based on intent-to-treat analysis); in addition, no difference in overall survival was observed between the groups.10005 A significant difference in estimated 4-year relapse-free survival was observed between patients randomized to receive exemestane and those randomized to receive placebo (96 versus 94%, respectively).10005 Exemestane treatment was associated with numerically, but not significantly, fewer local or metastatic recurrences and with a significant reduction in the incidence of new contralateral breast cancer, as compared with placebo.10005 An exploratory subset analysis suggested that the effect of exemestane on disease-free survival was greater in patients with tumors larger than 2 cm or with node-positive disease.10005 Although grade 3 adverse effects occurred more commonly in patients receiving exemestane, the incidence of grade 4 adverse effects was similar for patients receiving exemestane or placebo.10005
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
Advanced Breast Cancer in Postmenopausal Women
Exemestane is indicated for treatment of advanced breast cancer in postmenopausal women whose cancer has progressed after tamoxifen therapy.1, 16
Efficacy was evaluated in one comparative study (versus megestrol acetate) and 2 single-arm studies in postmenopausal women with advanced breast cancer that progressed after tamoxifen therapy for metastatic disease or as adjuvant therapy; some patients also received prior chemotherapy either for metastasis or as adjuvant therapy.1, 16 The studies evaluated objective response rates (complete and partial response); time to tumor progression (TTP) and overall survival also were assessed in the comparative study.1, 16 In the comparative study, objective response rates for exemestane and megestrol were comparable at 15 and 12.4%, respectively.1, 16 Response rates for exemestane in the 2 single-arm studies were 23.4 and 28.1%.1 In the comparative study, the median duration of response was 76.1 and 71 weeks for exemestane and megestrol, respectively, and the median TTP was 20.3 and 16.6 weeks, respectively.1, 16 No conclusions could be drawn related to overall survival differences with the limited study data available.1
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 HR-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
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 naïve to hormonal therapy.4000 Consult the ASCO guideline for additional information.4000
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.10010, 10011, 10013, 10017, 10023, 10026, 10052
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 | Treatment and Efficacy Measure | 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
Reduction in the Incidence of Breast Cancer in Women at High Risk†
Aromatase inhibitors, such as exemestane, have been used for the reduction in the incidence of breast cancer† among women who are at high risk of developing the disease.10050, 10051, 10055
In a randomized, placebo-controlled, double-blind trial (NCIC CTG MAP.3), 4560 postmenopausal women 35 years of age or older with at least one breast cancer risk factor (e.g., 60 years of age or older, Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ on breast biopsy or prior ductal carcinoma in situ treated with mastectomy) were randomly assigned to treatment with either exemestane (25 mg once daily) or placebo for 3 years.10051 The primary outcome was the incidence of invasive breast cancer.10051 After a median follow-up of 35 months, the annual incidence of invasive breast cancer was 0.19% with exemestane versus 0.55% with placebo (hazard ratio of 0.35).10051 The annual incidence of invasive and noninvasive (ductal carcinoma in situ) breast cancers was also lower with exemestane (annual incidence of 0.35% versus 0.77% with placebo; hazard ratio of 0.47).10051
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, exemestane is an alternative to tamoxifen or raloxifene in postmenopausal women (35 years of age or older) to reduce the risk of hormone receptor-positive invasive breast cancer.10050 Exemestane 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
Exemestane is administered orally once daily after a meal.1
Store at 25°C (excursions permitted between 15-30°C).1
Sequential Adjuvant Therapy for Postmenopausal Women with Early-stage Hormone Receptor-positive Breast Cancer
For sequential adjuvant treatment in postmenopausal women with early-stage hormone receptor-positive breast cancer, the recommended dosage of exemestane is 25 mg once daily.1 Exemestane is used in patients who have received 2-3 years of adjuvant tamoxifen therapy and are being switched to exemestane to complete a total of 5 consecutive years of adjuvant hormonal therapy.1
Advanced Breast Cancer in Postmenopausal Women
For treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy, the recommended dosage of exemestane is 25 mg once daily.1
Initial Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer†
For initial adjuvant therapy†, the dose of exemestane used has been 25 mg once daily for up to 10 years.10001, 10002, 10053
Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer†
For extended adjuvant therapy†, the dose of exemestane used has been 25 mg once daily for up to 10 years.10005
Adjuvant Therapy for Early-Stage Breast Cancer in Premenopausal Women in Combination with Ovarian Suppression†
For adjuvant therapy with ovarian suppression in early-stage breast cancer in premenopausal women†, the dose of exemestane used has been 25 mg once daily for 5 years.10010, 10011, 10052
Reduction in the Incidence of Breast Cancer in Women at High Risk†
For breast cancer risk reduction in undiagnosed women at risk†, the dose of exemestance used has been 25 mg once daily.10051
Dosage Modification for Concomitant Use with Drugs that Induce CYP3A4
Strong cytochrome P-450 (CYP) 3A4 inducers may decrease exemestane exposure.1 The recommended dosage of exemestane when given concurrently with strong CYP3A4 inducers (e.g., rifampin [rifampicin] or phenytoin) is 50 mg once daily after a meal.1
The AUC of exemestane is increased in patients with moderate or severe hepatic impairment (Child-Pugh B or C); however, dosage modification does not appear to be necessary.1
The AUC of exemestane is increased in patients with moderate or severe renal impairment (creatinine clearance less than 35 mL/minute per 1.73 m2); however, dosage modification does not appear to be necessary.1
The manufacturer makes no recommendations for dosage adjustments based on age.1
Known hypersensitivity to exemestane or any ingredient in the formulation.1
Reductions in Bone Mineral Density
Exemestane may cause a reduction in bone mineral density (BMD).1, 12 Postmenopausal women receiving an aromatase inhibitor as adjuvant therapy are at high risk for osteoporosis.12, 13 Following 2 years of adjuvant treatment with exemestane or tamoxifen, the reductions from baseline in lumbar spine and femoral neck BMD were 3.1 and 4.2%, respectively, in patients receiving exemestane and 0.2 and 0.3%, respectively, in those receiving tamoxifen.1 In a placebo-controlled trial, lumbar spine and femoral neck BMD were decreased by 3.5 and 4.6%, respectively, in patients receiving exemestane for 2 years, compared with 2.4 and 2.6%, respectively, in those receiving placebo.1 Concomitant bisphosphonate therapy and supplementation of vitamin D and calcium were not allowed in these clinical trials.1 In Intergroup Exemestane Study 031 (which was initiated after patients had completed 2-3 years of adjuvant tamoxifen therapy), patients switched to exemestane to complete 5 years of adjuvant therapy had a higher incidence of fracture during study treatment or posttreatment follow-up than did those who continued receiving tamoxifen (11 versus 8%).11
During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their BMD formally assessed by bone densitometry at the commencement of treatment.1 Patients should be monitored for BMD loss and treated as appropriate.1
Vitamin D (25-hydroxyvitamin D) levels should be assessed prior to beginning therapy with an aromatase inhibitor due to the high prevalence of vitamin D deficiency among women with breast cancer.1 Supplementation with vitamin D may be necessary.1
Administration with Estrogen-containing Agents
Systemic estrogen-containing agents should not be administered concomitantly with exemestane since these agents may interfere with the actions of exemestane.1
Grade 3 or 4 lymphocytopenia was reported in 20% of patients with advanced breast cancer receiving exemestane therapy; however, 89% of these patients had preexisting lower-grade lymphocytopenia, and 40% either recovered or improved to a lesser severity lymphopenia during exemestane therapy.1 Patients did not experience a substantial increase in viral infections, and no opportunistic infections were observed.1
In patients with early-stage breast cancer, hematologic abnormalities were reported less frequently in those receiving exemestane compared with those receiving tamoxifen; grade 3 or 4 abnormalities occurred rarely (about 0.1% of patients).1
Serum aminotransferase (AST, ALT), alkaline phosphatase, and γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations exceeding 5 times the upper limit of normal (i.e., grade 3 or worse) have been rarely reported in patients receiving exemestane for treatment of advanced breast cancer, but generally appear to be attributable to bone or liver metastasis.1 In one study, grade 3 or 4 elevations in GGT concentrations occurred in patients without evidence of liver metastasis in 3 or 2% of those receiving exemestane or megestrol acetate, respectively.1
In patients with early-stage breast cancer, elevated serum concentrations of bilirubin and alkaline phosphatase were reported more frequently in patients receiving exemestane (5-7 and 14-15%, respectively) compared with those receiving tamoxifen (0.8 and 3%, respectively) or placebo (0 and 7%, respectively).1 Grade 3-4 elevations in bilirubin concentrations occurred rarely in patients receiving exemestane (0.9%) or tamoxifen (0.1%).1
In clinical studies in patients with early-stage breast cancer, elevated serum creatinine concentrations were reported in 6% of patients receiving exemestane compared with 4% of those receiving tamoxifen and 0% of those receiving placebo.1
Because of concerns about possible incomplete estrogen suppression and reflex increases in gonadotrophin levels (ovarian hyperstimulation syndrome) in premenopausal women,6 the manufacturer states that exemestane is not indicated for the treatment of breast cancer in this population.1 However, exemestane has been used in combination with ovarian suppression† as adjuvant therapy in premenopausal women† with early-stage hormone receptor-positive breast cancer.10010, 10011, 10023
Fetal/Neonatal Morbidity and Mortality
Exemestane may cause fetal harm; the drug has been shown to be embryotoxic, fetotoxic, and abortifacient in animals.1 There are no adequate and well-controlled studies in pregnant women.1 The manufacturer recommends testing for pregnancy status within 7 days prior to initiation of exemestane, and females of reproductive potential should be advised to use effective contraceptive methods during exemestane therapy and for 1 month after discontinuance of the drug.1 If exemestane is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss.1
Exemestane may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 There are no adequate and well-controlled studies in pregnant women.1 If exemestane is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss.1
Exemestane is distributed into milk in rats; it is not known whether exemestane is distributed into human milk.1 Because of the potential for serious adverse effects in nursing infants, women should be advised to discontinue nursing during exemestane therapy and for at least 1 month after discontinuance of therapy.1 The effects of the drug on nursing infants or on milk production are unknown.1
Females and Males of Reproductive Potential
The manufacturer recommends testing for pregnancy status within 7 days prior to initiation of exemestane, and females of reproductive potential should be advised to use effective contraceptive methods during exemestane therapy and for 1 month after discontinuance of the drug.1
Results of animal studies suggest that exemestane may impair female and male fertility.1
Exemestane is not indicated in pediatric patients; safety and efficacy have not been established.1
No age-related alterations in the pharmacokinetics of exemestane have been identified in healthy postmenopausal women 43-68 years of age.1
Although the systemic exposure of exemestane is increased in patients with moderate or severe hepatic impairment, dosage adjustment does not appear to be necessary.1
Although the systemic exposure of exemestane is increased in patients with moderate or severe renal impairment, dosage adjustment does not appear to be necessary.1
Adverse events reported in 10% or more of patients with early-stage breast cancer receiving exemestane include hot flushes (flashes), fatigue, arthralgia, headache, insomnia, and increased sweating.1 Adverse events resulting in drug discontinuance occurred in similar proportions of exemestane- and tamoxifen-treated patients.1
Adverse events reported in 5% or more of patients with advanced breast cancer receiving exemestane include fatigue, nausea, and hot flushes.1 Most adverse events were mild to moderate in severity.1
Exemestane is metabolized by cytochrome P-450 isoenzyme 3A4 (CYP3A4).1 Exemestane does not inhibit CYP isoenzymes 1A2, 2C9, 2D6, 2E1, or 3A4.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Cytochrome P-450 Isoenzyme 3A4 Inhibitors
Concomitant administration of ketoconazole, a potent CYP3A4 inhibitor, and exemestane did not substantially alter the pharmacokinetics of exemestane.1 Therefore, clinically important pharmacokinetic interactions between exemestane and CYP3A4 inhibitors appear to be unlikely.1
Cytochrome P-450 Isoenzyme 3A4 Inducers
Concomitant use of exemestane with inducers of CYP3A4 may result in decreased systemic exposure of exemestane.1 Administration of the potent CYP3A4 inducer rifampin (600 mg daily for 14 days) followed by exemestane (single 25-mg dose) resulted in a 41% decrease in peak plasma concentrations and a 54% decrease in systemic exposure of exemestane.1 Concomitant use of other CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, St. John's wort [ Hypericum perforatum ]) also may result in decreased exposure to exemestane.1 An increase in exemestane dosage to 50 mg once daily after a meal is recommended in patients receiving concomitant therapy with a potent CYP3A4 inducer (e.g., phenytoin, rifampin).1
Because estrogens may diminish the pharmacologic action of exemestane, the drugs should not be used concomitantly.1
Exemestane is an irreversible, selective steroidal aromatase inhibitor structurally related to the natural substrate androstenedione.1, 2, 3, 4, 5, 6 Unlike nonsteroidal (type II) aromatase inhibitors (e.g., aminoglutethimide, letrozole), steroidal inhibitors such as exemestane (type I aromatase inhibitors) act as false substrates and are converted by aromatase to reactive alkylating intermediates that bind covalently to the substrate binding site of the enzyme; this binding to the active site of aromatase is irreversible, resulting in its inactivation (i.e., “suicide” inhibition).1, 2, 4, 5, 6 As a result of these differences, there appears to be a lack of cross-resistance in susceptible cancers between type I and II inhibitors.2, 4
Exemestane selectively inhibits the conversion of androgens to estrogens.1, 2, 4, 5, 6 Because estrogen acts as a growth factor for hormone-dependent breast cancer cells, reduction of serum and tumor concentrations of estrogen inhibits tumor growth and delays disease progression.1, 6 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, 6 Exemestane selectively inhibits the synthesis of estrogens and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.1, 2, 3, 6 In dose-ranging (0.5-800 mg) studies, 25 mg was the minimum dose to exhibit maximum suppression of plasma estrogens.3, 6 A single 25-mg exemestane dose reduces plasma estrogen (estradiol, estrone, and estrone sulfate) concentrations in postmenopausal women by as much as 85-95% within 2-3 days, with maximal suppression persisting up to at least 4-5 days after dosing.1, 3 After 4-12 weeks of exemestane therapy (25 mg daily) in postmenopausal women, plasma estrogen concentrations were suppressed by an average of 91-95%,2, 6 and whole body aromatization was suppressed by 98%.1, 6 Although an apparently lower suppression (e.g., by 60-70%) of plasma estrogens has been reported in some studies, these studies used a less-specific assay method (i.e., RIA) than the method (i.e., HPLC) used in studies reporting higher levels of suppression.2, 3, 4
A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with exemestane dosages of 2.5 mg or more daily.1, 2 Slight, dose-independent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations have been observed even at low dosages as a result of negative feedback on the pituitary gland.1, 2, 3 At dosages up to 25 mg daily, no clinically important effect on circulating concentrations of androstenedione, dehydroepiandrostenedione sulfate, or 17-hydroxyprogesterone and only small decreases in circulating concentrations of testosterone are observed; however, at dosages of 200 mg or more daily, testosterone and androstenedione concentrations are increased.1, 3 17-Hydroexemestane, a metabolite, exhibits substantial intrinsic androgenic activity, which may become clinically important at high (e.g., 200 mg daily) exemestane dosages.1, 2, 3
Exemestane is rapidly absorbed following oral administration, with peak concentrations in women with breast cancer or healthy women attained within about 1.2 or 2.9 hours, respectively.1 Approximately 42% of an oral dose of exemestane is absorbed from the gastrointestinal tract.1 Following repeated doses, the mean AUC in women with breast cancer is approximately twice that in healthy women.1 Administration with a high-fat meal increases the AUC and peak plasma concentration of exemestane by 59 and 39%, respectively.1 Exemestane is approximately 90% protein bound (mainly to α1-acid glycoprotein and albumin).1 Exemestane is extensively metabolized via CYP3A4 and aldoketoreductases; metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug.1 One metabolite, 17-hydroexemestane, may have androgenic activity.1 Exemestane is excreted similarly (42%) in both urine and feces; <1% is excreted as unchanged drug in urine.1 The half-life of exemestane is approximately 24 hours.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 | 25 mg* | ||
Exemestane Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Pharmacia and Upjohn Company division of Pfizer. Aromasin® (exemestane) tablets prescribing information. New York, NY; 2021 Nov.
2. Johannessen DC, Engan T, Di Salle E et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res . 1997; 3:1101-8. [PubMed 9815789]
3. Evans TRJ, Di Salle E, Ornati G et al. Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res . 1992; 52:5933-9. [PubMed 1394219]
4. Geisler J, King N, Anker G et al. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res . 1998; 4:2089-93. [PubMed 9748124]
5. Reddy P. A review of the newer aromatase inhibitors in the management of metastatic breast cancer. J Clin Pharm Ther . 1998; 23:81-90. [PubMed 9786093]
6. Goss PE, Gwyn KMEH. Current perspectives on aromatase inhibitors in breast cancer. J Clin Oncol . 1994; 12:2460-70. [PubMed 7964964]
7. Anker GB, Refsum H, Ueland PM et al. Influence of aromatase inhibitors on plasma total homocysteine in postmenopausal breast cancer patients. Clin Chem . 1999; 45:252-6. [PubMed 9931048]
8. Coombes RC, Hall E, Gibson LJ et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med . 2004; 350:1081-92. [PubMed 15014181]
9. Coombes RC, Kilburn LS, Snowdon CF et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet . 2007; 369:559-70. [PubMed 17307102]
10. Burstein HJ, Prestrud AA, Seidenfeld J et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol . 2010; 28:3784-96. [PubMed 20625130][PubMedCentral]
11. Bliss JM, Kilburn LS, Coleman RE et al. Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study. J Clin Oncol . 2012; 30:709-17. [PubMed 22042946]
12. Gaillard S, Stearns V. Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management. Breast Cancer Res . 2011; 13:205. [PubMed 21457526][PubMedCentral]
13. Hilner BE, Ingle JN, Chelbowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol . 2003; 21:4042-57. [PubMed 12963702]
14. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med . 2003; 349: 1793-802. [PubMed 14551341]
15. Reviewers' comments (personal observations) on letrozole.
16. Kaufmann M, Bajetta E, Dirix LY et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol . 2000; 18:1399-411. [PubMed 10735887]
17. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2011 Nov 21.
70. Hadji P, Aapro MS, Body JJ et al. Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment. Ann Oncol . 2011; 22:2546-55. [PubMed 21415233]
71. Reid DM, Doughty J, Eastell R et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev . 2008; 34 Suppl 1:S3-18. [PubMed 18515009]
72. Aapro M, Abrahamsson PA, Body JJ et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol . 2008; 19:420-32. [PubMed 17906299]
73. Body JJ, Bergmann P, Boonen S et al. Management of cancer treatment-induced bone loss in early breast and prostate cancer -- a consensus paper of the Belgian Bone Club. Osteoporos Int . 2007; 18:1439-50. [PubMed 17690930]
74. Hadji P, Aapro MS, Body JJ et al. Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol . 2017; 7:1-12. [PubMed 28413771]
4000. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol . 2021;39(35):3959-3977.
10001. van de Velde CJ, Rea D, Seynaeve C et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet . 2011; 377:321-31. [PubMed 21247627]
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]
10003. Suppression of ovarian function and either tamoxifen or exemestane with or without chemotherapy in treating premenopausal women with resected breast cancer (PERCHE). From ClinicalTrials.gov Registry. Accessed 2013 Dec 12.
10004. Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol . 2002; 20:3317-27. [PubMed 12149306]
10005. Mamounas EP, Jeong JH, Wickerham DL et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol . 2008; 26:1965-71. [PubMed 18332472]
10006. Letrozole in Treating Women With Primary Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy. Clinical Trials (PDQ) (database). Bethesda, MD: National Cancer Institute; 2014 Jan 13.
10007. Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol . 2005; 23:619-29. [PubMed 20625130]
10008. AHFS Final Determination: Exemestane for initial adjuvant treatment of early-stage breast cancer. Published 2014 June.
10009. AHFS Final Determination: Exemestane for extended adjuvant treatment of early-stage breast cancer. Published 2014 June.
10010. Francis PA, Regan MM, Fleming GF et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med . 2015; 372:436-46. [PubMed 25495490]
10011. Pagani O, Regan MM, Walley BA et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med . 2014; 371:107-18. [PubMed 24881463]
10012. Francis PA, Pagani O, Fleming GF et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med . 2018; 379:122-137. [PubMed 29863451]
10013. Tevaarwerk AJ, Wang M, Zhao F et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol . 2014; 32:3948-58. [PubMed 25349302]
10016. Pan K, Bosserman LD, Chlebowski RT. Ovarian Suppression in Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. J Clin Oncol . 2019; 37:858-861. [PubMed 30742565]
10017. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. J Clin Oncol . 2016; 34:1689-701. [PubMed 26884586]
10019. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol . 2019; 37:423-438. [PubMed 30452337]
10020. Dowsett M, Lønning PE, Davidson NE. Incomplete Estrogen Suppression With Gonadotropin-Releasing Hormone Agonists May Reduce Clinical Efficacy in Premenopausal Women With Early Breast Cancer. J Clin Oncol . 2016; 34:1580-3. [PubMed 26729430]
10023. Gnant M, Mlineritsch B, Stoeger H et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol . 2011; 12:631-41. [PubMed 21641868]
10024. Gnant M, Mlineritsch B, Stoeger H et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol . 2015; 26:313-20. [PubMed 25403582]
10025. Bellet M, Gray KP, Francis PA et al. Twelve-Month Estrogen Levels in Premenopausal Women With Hormone Receptor-Positive Breast Cancer Receiving Adjuvant Triptorelin Plus Exemestane or Tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy. J Clin Oncol . 2016; 34:1584-93. [PubMed 26729437]
10026. Perrone F, De Laurentiis M, De Placido S et al. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. Eur J Cancer . 2019; 118:178-186. [PubMed 31164265]
10027. Chlebowski RT, Pan K, Col NF. Ovarian suppression in combination endocrine adjuvant therapy in premenopausal women with early breast cancer. Breast Cancer Res Treat . 2017; 161:185-190. [PubMed 27785653]
10028. AHFS final determination of medical acceptance: Off-label use of endocrine therapy in combination with ovarian suppression for the adjuvant treatment of early-stage hormone receptor-positive breast cancer in premenopausal women. Published January 4, 2021.
10050. Visvanathan K, Fabian CJ, Bantug E et al. Use of endocrine therapy for breast cancer risk reduction: ASCO Clinical Practice Guideline update. J Clin Oncol . 2019; 37:3152-3165.. [PubMed 31479306]
10051. Goss PE, Ingle JN, Alés-Martínez JE et al; NCIC CTG MAP.3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381-2391. [PubMed 21639806]
10052. Bradley R, Braybrooke J, Gray R et al; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 2022;23(3):382-392. [PubMed 35123662]
10053. De Placido S, Gallo C, De Laurentiis M et al; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018;19(4):474-485. [PubMed 29482983]
10054. Morden JP, Alvarez I, Bertelli G et al. Long-Term Follow-Up of the Intergroup Exemestane Study. J Clin Oncol. 2017;35(22):2507-2514. [PubMed 28467729]
10055. Nelson HD, Fu R, Zakher B et al. Medication use for the risk reduction of primary breast cancer in women. Updated evidence report and systematic review for US Preventive Services Task Force. JAMA. 2019;322(9):868-886. [PubMed 31479143]
10056. Derks MGM, Blok EJ, Seynaeve C et al. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(9):1211-1220. [PubMed 28732650]
10075. Burstein HJ, Prestrud AA, Seidenfeld J et al; American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010;28(23):3784-3796. [PubMed 20625130]