- Email: [email protected]
Aromatase Inhibitors in Breast Cancer Therapy
Aromatase Inhibitors in Breast Cancer Therapy Aman U. Buzdar Abstract Recent advances have been made in the hormonal treatment of breast cancer with the advent of thirdgeneration aromatase inhibitors (anastrozole, letrozole, and exemestane). These newer agents have substantial antitumor activity and appear to be as effective as tamoxifen, with fewer adverse effects. Recent reports indicate that anastrozole is more effective than tamoxifen as adjuvant endocrine therapy in postmenopausal women with breast cancer. This report provides an overview of the clinical trials conducted to date with the aromatase inhibitors as first- and second-line therapies, with an emphasis on recently updated analyses comparing anastrozole with tamoxifen in the adjuvant setting. Clinical Breast Cancer, Vol. 4, Suppl. 2, S84-S88, November 2003 Key words: Anastrozole, Aromatase inhibitors, Exemestane, Letrozole, Tamoxifen
Introduction Antiestrogen hormonal therapies are a critical component of breast cancer management. Tamoxifen, which blocks estrogen signals at the receptor level, has been extensively used worldwide. When administered for 5 years to patients with early breast cancer, tamoxifen resulted in a 47% relative risk reduction for disease recurrence and a 26% relative risk reduction for mortality.1 In postmenopausal women with estrogenreceptor (ER) positive breast cancer, tamoxifen acts predominantly as an antagonist at the ER; however, because of its partial agonist activity, it allows some estrogenlike signaling. This partial agonist effect may be responsible for the increased risks of proliferative endometrial cancer and thromboembolic disorders associated with tamoxifen therapy and may ultimately limit its clinical efficacy compared with newer agents.2 Recent attention has focused on the third-generation aromatase inhibitors (eg, anastrozole, exemestane, and letrozole), which exert their antiestrogen effects by inhibiting the conversion of adrenal androgen substrates (the main estrogen source in postmenopausal women) to estrogen. The aromatase inhibitors represent a significant advancement mechanistically because these agents are more selective in reducing the estrogen than are other therapies. The aromatase inhibitors result in profound estrogen deprivation and virtually obliterate any ER signaling.3 Recent trials evaluating aromatase inhibitors in patients with breast cancer are discussed herein.
Aromatase Inhibitors in Advanced Breast Cancer Based on fairly large, multicenter studies, aromatase inhibiThe University of Texas M. D. Anderson Cancer Center, Houston, Texas Submitted: Oct 2, 2003; Revised: Oct 29, 2003; Accepted: Nov 3, 2003 Address for correspondence: Aman Buzdar, MD, Department of Breast Medical Oncology, Box 424, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-794-4385; e-mail: [email protected]
S84 • Clinical Breast Cancer Supplement November 2003
tors first became available as second-line agents for the treatment of advanced breast cancer in postmenopausal women with tamoxifen-resistant disease.2 All of these studies showed evidence of a survival advantage favoring aromatase inhibitors over megestrol acetate (Figure 1).4-7 The duration of clinical benefit (defined as a complete response [CR], partial response [PR], or stable disease [SD]) in patients treated with an aromatase inhibitor ranged from 18 to 24 weeks compared with 11 to 16 weeks in patients receiving megestrol acetate. These studies were the first to provide evidence that newer agents are more effective and better tolerated than are older endocrine agents, thus challenging the paradigm that all hormones are alike.
Efficacy as First-Line Therapy Given their success as second-line therapy, the next logical step was to evaluate aromatase inhibitors as first-line therapy in advanced disease.
Buzdar et al4
22.5
MA AN
26.7
6
Dombernowsky et al
25.8
LE MA
21.5
Kaufmann et al7 EXE NR MA
28.4
5
Buzdar et al
LE (2.5 mg) LE (0.5 mg)
29 33
MA 0
26
5
10
15
20
25
30
Median Time to Death (Months) Abbreviations: AN = anastrozole; EXE = exemestane; LE = letrozole; MA = megestrol acetate
35
Anastrozole. Two pivotal studies, one Number of Clinical Median TTP North American study8 and one larger Trial CR PR Patients Benefit* (Months) international study,9 compared the efficacy and safety of anastrozole 1
mg once daily with tamoxifen 20 mg Anastrozole 2.9% 18.1% 59.1% 11.1 171 once daily in postmenopausal patients Tamoxifen 5.6 2.7% 14.3% 45.6% 182 with advanced breast cancer (ER-posi2 tive or ER-unknown status). In the North American study (n = 353), Anastrozole 8.2 5.6% 27.4% 56.2% 340 first-line therapy with anastrozole Tamoxifen 8.3 4.9% 27.7% 55.5% 328 prolonged median time to progres sion compared with tamoxifen (11.1 months vs. 5.6 months, respectively; Letrozole 9.3 8.0% 23.0% 49.0% 453 P = 0.005).8 Clinical benefit rates (CR Tamoxifen 6.0 3.0% 17.0% 38.0% 454 + PR + SD ≥ 24 weeks) were similar between the agents (59.1% vs. 45.6%, for anastrozole and tamoxifen, respecExemestane 8.9 10.0% 32.0% 58.0% 31 tively) (Table 1).10-12 Thromboembolic Tamoxifen 5.2 3.0% 13.0% 31.0% 32 events (4.1% vs. 8.2%) and vaginal bleeding (1.2% vs. 3.8%) were reported *Clinical benefit = CR + PR + SD 24 weeks in fewer patients receiving anastrozole = 0.005 = 0.0001 than tamoxifen. In the international Abbreviations: CR = complete response; PR = partial response; SD = stable disease; TTP = time to progression trial (n = 668), the median time to disin the tamoxifen arm.14 A unique aspect of this trial was the ease progression was not statistically option to cross over to the other treatment if the patient had different between anastrozole and tamoxifen (8.2 months disease progression and continued to be an appropriate candivs. 8.3 months, respectively; P = 0.941). Clinical benefit rates date for endocrine therapy.11 Because 43% of patients crossed were equivalent (anastrozole, 56.2% vs. tamoxifen, 55.5%) 9 over during the trial, the reported survival estimates may have (Table 1). Similar to the North American trial, rates of thromboembolic events and vaginal bleeding were higher in the underestimated the benefit of letrozole therapy.10 Similar to 9 tamoxifen group. A combined analysis of these trials showed findings in the anastrozole trials, patients with ER-positive that anastrozole was as effective as tamoxifen in the intent-todisease treated with letrozole had a significantly better retreat (ITT) population, with a decreased risk of thromboemsponse than did patients treated with tamoxifen.11 Letrozole also has been studied in postmenopausal women bolic disease and vaginal bleeding, and significantly prolonged with primary breast cancer who had completed approximately time to disease progression compared with tamoxifen observed 5 years of therapy with tamoxifen.15 Patients were randomin patients with ER-positive disease.2,13 Upon further examination of these data, a clear pattern ized to letrozole 2.5 mg (n = 2575) or placebo (n = 2582) for emerges in patients with ER-positive disease. In the inter5 years. However, because there was a significant disease-free national anastrozole trial showing equivalence between the survival benefit for letrozole compared with placebo at the first agents, receptor status was unknown in more than 50% of interim analysis, the study was concluded after patients had a patients.9 In the North American trial favoring anastrozole, median follow-up of 2.4 years. There were 75 recurrences or nearly 90% of patients were ER positive.8 Thus, patients with new breast cancers in the letrozole group compared with 132 ER-positive disease appear to derive a longer duration of cliniin the placebo group (hazard ratio 0.57; 95% confidence intercal benefit with anastrozole versus tamoxifen therapy. val: 0.43-0.75; P = 0.00008). The estimated 4-year disease-free survival rate was 93% and 87% (P ≤0.001) in the letrozole and Letrozole. Letrozole 2.5 mg once daily was compared with placebo groups, respectively. tamoxifen 20 mg once daily in 907 postmenopausal patients with advanced breast cancer.11 Sixty-five percent of patients Exemestane. Exemestane, the steroidal aromatase inhibitor, had ER-positive or progesterone receptor–positive tumors. is currently undergoing phase III trials. Preliminary results Clinical benefit rates (CR + PR + SD ≥24 weeks) were sigof a small phase II trial comparing exemestane and tamoxinificantly higher in the letrozole group (49%) compared with fen as first-line therapy in 63 postmenopausal patients with the tamoxifen group (38%) (P = 0.001; Table 1). Median metastatic breast cancer are available. Exemestane had an time to progression was significantly longer in the letrozole objective response rate of 42% vs. 16% for tamoxifen. Clinical group compared with the tamoxifen group (9.3 months vs. 6.0 benefit (CR + PR + SD ≥24 weeks) rates were also higher for months, respectively; P = 0.0001).11 Median overall survival in exemestane than tamoxifen (58% vs. 31%). Median time to this trial was 34 months in the letrozole arm and 30 months progression was 8.9 months vs. 5.2 months, respectively.10,12
Clinical Breast Cancer Supplement November 2003
• S85
Aromatase Inhibitors in Breast Cancer Postmenopausal women with invasive breast cancer
Aromatase Inhibitors in the Adjuvant Setting: The ATAC Trial
Surgery radiotherapy chemotherapy Randomization 1:1:1
Anastrozole 1 mg qd + Placebo
Tamoxifen 20 mg qd + Placebo
Anastrozole 1 mg qd + Tamoxifen 20 mg qd
Regular follow-up
Primary trial endpoints
Secondary trial endpoints
• Disease-free survival
• Incidence of contralateral breast cancer
• Safety/tolerability
• Time to distant recurrence • Survival
Taken together, these clinical trials demonstrate that the nonsteroidal aromatase inhibitors should be considered as first-line therapy for postmenopausal women with advanced breast cancer.
Tolerability In general, third-generation aromatase inhibitors are very well tolerated. These newer agents have fewer adverse effects, largely because they are relatively inert compounds. The most common adverse events include hot flashes and gastrointestinal complaints (eg, nausea and vomiting).10 Unlike tamoxifen, these agents, particularly the nonsteroidal aromatase inhibitors (eg, anastrozole, letrozole), lack intrinsic agonist properties. As reported in the first-line therapy trials, there was a consistently lower risk of thromboembolic events and less vaginal bleeding with the aromatase inhibitors than with
$'("#$%)'!$ ( $!!$+ # . !(&!$$% $&($", . ,&' . ,&'+ ( # #(()(&)'#"#$&& $& "$#( ' . "#$&& $&"$#( ' $!! )!&'( ")!( # $&"$# $##(&( $#'+ ( #( %$'("#$%)'!&# '($!$ !!,%&$*#$%&! #*' * '' '(&$ #&%($&-%$' ( *'(&$ #&%($&-# ( *$&)# #$+#'(()' $* #$ "('(( ''
S86 • Clinical Breast Cancer Supplement November 2003
tamoxifen.8,9,11 These findings are of particular importance when considering the use of these novel agents in the adjuvant setting.
Based on their excellent activity as firstand second-line therapies in the setting of advanced disease, third-generation aromatase inhibitors are being evaluated in the adjuvant setting in early breast cancer. The first of these studies to be reported is the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial.2 This randomized, multicenter study compared anastrozole 1 mg daily, tamoxifen 20 mg daily, or daily anastrozole 1 mg and tamoxifen 20 mg in a 1:1:1 combination (Figure 2). Eligible patients were postmenopausal, had histologically documented invasive breast cancer that was operable, had completed primary surgery and chemotherapy, and were candidates for adjuvant hormonal therapy (Table 2).
Efficacy The primary endpoints of the trial were disease-free survival and safety and tolerability.2 Disease-free survival was defined as the time to the earliest occurrence of local or distant recurrence, new primary breast cancer, or death from any cause. Secondary endpoints included time to recurrence, incidence of new contralateral primary breast tumors, distant recurrence, and overall survival. Patients were assessed for efficacy and safety at study entry, at 3 months, at 6 months, and every 6 months thereafter for up to 5 years, then annually for up to 10 years. The primary endpoint of disease-free survival was used to determine study sample size.2 For noninferiority to be concluded between anastrozole and tamoxifen, 352 events per group were needed to achieve > 90% power. The main data analysis took place after a total of 1056 first events. The first results in 9366 patients (anastrozole, n = 3125; tamoxifen, n = 3116; combination, n = 3125) were reported in June 2002, with a median follow-up at approximately 33 months. An updated analysis of the study was performed at a 47month follow-up (Figure 3) at which the number of first events increased from 1079 to 1373.16 In ER-positive patients, who account for 84% of all patients, the number of first events increased from 766 to 991 between the 33-month and 47-month analyses. First events that occurred in the ITT and ER-positive populations are summarized in Table 3. In the updated ITT analysis focusing on the anastrozole and tamoxifen arms only, the time-to-first-event curves continue to diverge (Figure 4). The absolute differences between treatments in the time to first event were 1.5% at the 3-year follow-up and 2.4% at the 4-year follow-up.16 Similarly, the absolute differences between treatments in the time to recurrence were 1.7% and 2.3% at the 3- and 4-year followup periods, respectively. Likewise, in the ER-positive
Aman U. Buzdar patients, consistent results were observed. At the 3- and 4-year follow-up periods, the absolute differences in the time to first event (1.7% vs. 2.9%, respectively) and time to recurrence (1.8% and 2.6%, respectively) increased over time, with proportional hazard reductions of 17% for the risk of a first event and 22% for the risk of a recurrence with anastrozole over tamoxifen therapy. It is of note that the tamoxifen event rate, when adjusted for nodal status, was nearly identical in both the ATAC2 and Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)1 trials, suggesting that the improved efficacy observed with anastrozole was due to enhanced antitumor activity rather than a suboptimal performance of tamoxifen.2
ITT Population Anastrozole (n = 3125)
Tamoxifen (n = 3116)
Anastrozole (n = 2617)
Tamoxifen (n = 2598)
413 (13.2%)
472 (15.1%)
290 (11.1%)
345 (13.3%)
84 (2.7%)
101 (3.2%)
48 (1.8%)
62 (2.4%)
195 (6.2%)
222 (7.1%)
133 (5.1%)
158 (6.1%)
20 (0.6%)
35 (1.1%)
17 (0.6%)
31 (1.2%)
Event
Invasive Ductal carcinoma in situ
5 (0.2%)
5 (0.2%)
3 (0.1%)
4 (0.2%)
109 (3.5%)
109 (3.5%)
88 (3.4%)
90 (3.5%)
# !$ ! # ! " Abbreviations: ATAC = Arimidex, Tamoxifen Alone or in Combination; ER = estrogen receptor; ITT = intent to treat
Safety and Tolerability Much of the available data suggest that, compared with tamoxifen, anastrozole therapy results in significantly fewer postmenopausal symptoms, including hot flashes, vaginal discharge, vaginal bleeding, thromboembolic events, ischemic cerebrovascular events, and endometrial cancer.2 This can be partly explained by the lack of agonist activity of aromatase inhibitors. Symptoms sometimes characterized as minor, such as vaginal bleeding, often result in a cascade of potentially avoidable events. In particular, a vaginal bleeding episode in a postmenopausal woman often leads to a full workup, including ultrasonography, dilation and curettage, and biopsy to diagnostically rule out endometrial cancer. Reductions in
100
90
80
70 60 50
40 30 20 10 0
1
2
ER-Positive Population
3
4
5
the occurrence of these events with anastrozole use are likely to avoid unnecessary anxiety and health-care costs. A second concern is the risk of endometrial cancer with long-term use of tamoxifen, and it is of substantial importance that a nearly 70% reduction in the incidence of endometrial carcinoma was noted in the anastrozole group in the ATAC trial.16 Additionally, the incidence of other primary cancers (eg, colorectal, head and neck, lung, melanoma, ovary, and skin) was similar across treatment groups. Last, substantial risk reductions were associated with anastrozole over treatment with tamoxifen alone with respect to ischemic events (53%; odds ratio 0.47; P = 0.0006) and thromboembolic events (42%; odds ratio 0.58; P = 0.0006), respectively. Based on the findings in the ATAC trial, only two events favored tamoxifen over anastrozole treatment: joint stiffness and musculoskeletal discomfort, which appear to be a class effect of the aromatase inhibitors, and an increased risk of bone-related fractures.2 The incidence of hip fractures appears to be similar across the two treatments; rib and spinal fractures were less common in patients treated with tamoxifen.2 Fractures may be the result of a dual effect: loss of the protective partial-agonist effect of tamoxifen on bone and estrogen deprivation caused by aromatase inhibitors. Patients should be informed of these risks, with physicians assessing the need for a baseline bone density test and appropriate follow-up, intervention, or both. Overall, nearly 90% of patients adhered to therapy, with significantly fewer patients in the anastrozole group discontinuing treatment due to an adverse event (anastrozole 7.8% vs. tamoxifen 11.1% vs. combination 10.9%; P < 0.0001).16 The fact that significantly fewer adverse events occurred in patients treated with anastrozole is of particular importance for its potential long-term use in the adjuvant setting.2
Conclusion Aromatase inhibitors are clearly beneficial in postmenopausal women with advanced breast cancer, particularly those with ER-positive tumors. Based on the available data to date, there is also a choice of adjuvant endocrine therapy for post-
Clinical Breast Cancer Supplement November 2003
• S87
Aromatase Inhibitors in Breast Cancer $ " ! ! # $ $ ! 20
AN vs TAM
HR
95% CI
value
0.86
0.76-0.99
0.030
15 Anastrozole Tamoxifen 10
5
0
6
12
18
24
Absolute Difference 1.5 %
Absolute Difference 2.4 %
30
42
36
48
54
1489 1452
726 703
Number of Patients at Risk AN 3125 TAM 3116
2997 2991
2861 2821
2634 2577
! ! !! $ "% !!! " ! ! $ " ! # Abbreviations: AN = anastrozole; CI = confidence interval; HR = hazard ratio; TAM = tamoxifen
menopausal women with hormone-responsive tumors. The initial findings from the ATAC trial, which were consistently supported in the updated analysis, demonstrate a significant improvement in disease-free survival and improved safety and tolerability with anastrozole compared with tamoxifen.2 Future and ongoing studies will further define the role of the aromatase inhibitors for adjuvant therapy of early breast cancer and in women at increased risk of breast cancer.
References
1. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451-1467. 2. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:2131-2139.
S88 • Clinical Breast Cancer Supplement November 2003
3. Geisler J, King N, Dowsett M, et al. Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer 1996; 74:1286-1291. 4. Buzdar AU, Jonat W, Howell A, et al, for the Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer 1998; 83:1142-1152. 5. Buzdar A, Douma J, Davidson N, et al. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 2001; 19:3357-3366. 6. Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998; 16:453-461. 7. Kaufmann M, Bajetta E, Dirix LY, et al, for the Exemestane Study Group. 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. J Clin Oncol 2000; 18:1399-1411. 8. Nabholtz JM, Buzdar A, Pollak M, et al, for the Arimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758-3767. 9. Bonneterre J, Thurlimann B, Robertson JFR, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000; 18:3748-3757. 10. Assikis VJ, Buzdar A. Recent advances in aromatase inhibitor therapy for breast cancer. Semin Oncol 2002; 29 (suppl 11):120-128. 11. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596-2606. 12. Paridaens R, Dirix LY, Beex L, et al. Exemestane (Aromasin) is active and well tolerated as first-line hormonal therapy (HT) of metastatic breast cancer (MBC) patients (Pts): results of a randomized phase II trial. Proc Am Soc Clin Oncol 2000; 19:83a (Abstract #316). 13. Buzdar A, Nabholtz JM, Robertson JF, et al. Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer (Abc) in postmenopausal (Pm) women—combined analysis from two identically designed multicenter trials. Proc Am Soc Clin Oncol 2000; 19:154a (Abstract #609D). 14. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21:21012109. 15. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for earlystage breast cancer. N Engl J Med 2003;349:1793-1802. 16. Buzdar A. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial in postmenopausal women with early breast cancer–updated efficacy results based on a medial follow-up of 47 months (abstract). Breast Cancer Res Treatment 2003; 77:295. 17. Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98:1779-1781.
Introduction Antiestrogen hormonal therapies are a critical component of breast cancer management. Tamoxifen, which blocks estrogen signals at the receptor level, has been extensively used worldwide. When administered for 5 years to patients with early breast cancer, tamoxifen resulted in a 47% relative risk reduction for disease recurrence and a 26% relative risk reduction for mortality.1 In postmenopausal women with estrogenreceptor (ER) positive breast cancer, tamoxifen acts predominantly as an antagonist at the ER; however, because of its partial agonist activity, it allows some estrogenlike signaling. This partial agonist effect may be responsible for the increased risks of proliferative endometrial cancer and thromboembolic disorders associated with tamoxifen therapy and may ultimately limit its clinical efficacy compared with newer agents.2 Recent attention has focused on the third-generation aromatase inhibitors (eg, anastrozole, exemestane, and letrozole), which exert their antiestrogen effects by inhibiting the conversion of adrenal androgen substrates (the main estrogen source in postmenopausal women) to estrogen. The aromatase inhibitors represent a significant advancement mechanistically because these agents are more selective in reducing the estrogen than are other therapies. The aromatase inhibitors result in profound estrogen deprivation and virtually obliterate any ER signaling.3 Recent trials evaluating aromatase inhibitors in patients with breast cancer are discussed herein.
Aromatase Inhibitors in Advanced Breast Cancer Based on fairly large, multicenter studies, aromatase inhibiThe University of Texas M. D. Anderson Cancer Center, Houston, Texas Submitted: Oct 2, 2003; Revised: Oct 29, 2003; Accepted: Nov 3, 2003 Address for correspondence: Aman Buzdar, MD, Department of Breast Medical Oncology, Box 424, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-794-4385; e-mail: [email protected]
S84 • Clinical Breast Cancer Supplement November 2003
tors first became available as second-line agents for the treatment of advanced breast cancer in postmenopausal women with tamoxifen-resistant disease.2 All of these studies showed evidence of a survival advantage favoring aromatase inhibitors over megestrol acetate (Figure 1).4-7 The duration of clinical benefit (defined as a complete response [CR], partial response [PR], or stable disease [SD]) in patients treated with an aromatase inhibitor ranged from 18 to 24 weeks compared with 11 to 16 weeks in patients receiving megestrol acetate. These studies were the first to provide evidence that newer agents are more effective and better tolerated than are older endocrine agents, thus challenging the paradigm that all hormones are alike.
Efficacy as First-Line Therapy Given their success as second-line therapy, the next logical step was to evaluate aromatase inhibitors as first-line therapy in advanced disease.
Buzdar et al4
22.5
MA AN
26.7
6
Dombernowsky et al
25.8
LE MA
21.5
Kaufmann et al7 EXE NR MA
28.4
5
Buzdar et al
LE (2.5 mg) LE (0.5 mg)
29 33
MA 0
26
5
10
15
20
25
30
Median Time to Death (Months) Abbreviations: AN = anastrozole; EXE = exemestane; LE = letrozole; MA = megestrol acetate
35
Anastrozole. Two pivotal studies, one Number of Clinical Median TTP North American study8 and one larger Trial CR PR Patients Benefit* (Months) international study,9 compared the efficacy and safety of anastrozole 1
mg once daily with tamoxifen 20 mg Anastrozole 2.9% 18.1% 59.1% 11.1 171 once daily in postmenopausal patients Tamoxifen 5.6 2.7% 14.3% 45.6% 182 with advanced breast cancer (ER-posi2 tive or ER-unknown status). In the North American study (n = 353), Anastrozole 8.2 5.6% 27.4% 56.2% 340 first-line therapy with anastrozole Tamoxifen 8.3 4.9% 27.7% 55.5% 328 prolonged median time to progres sion compared with tamoxifen (11.1 months vs. 5.6 months, respectively; Letrozole 9.3 8.0% 23.0% 49.0% 453 P = 0.005).8 Clinical benefit rates (CR Tamoxifen 6.0 3.0% 17.0% 38.0% 454 + PR + SD ≥ 24 weeks) were similar between the agents (59.1% vs. 45.6%, for anastrozole and tamoxifen, respecExemestane 8.9 10.0% 32.0% 58.0% 31 tively) (Table 1).10-12 Thromboembolic Tamoxifen 5.2 3.0% 13.0% 31.0% 32 events (4.1% vs. 8.2%) and vaginal bleeding (1.2% vs. 3.8%) were reported *Clinical benefit = CR + PR + SD 24 weeks in fewer patients receiving anastrozole = 0.005 = 0.0001 than tamoxifen. In the international Abbreviations: CR = complete response; PR = partial response; SD = stable disease; TTP = time to progression trial (n = 668), the median time to disin the tamoxifen arm.14 A unique aspect of this trial was the ease progression was not statistically option to cross over to the other treatment if the patient had different between anastrozole and tamoxifen (8.2 months disease progression and continued to be an appropriate candivs. 8.3 months, respectively; P = 0.941). Clinical benefit rates date for endocrine therapy.11 Because 43% of patients crossed were equivalent (anastrozole, 56.2% vs. tamoxifen, 55.5%) 9 over during the trial, the reported survival estimates may have (Table 1). Similar to the North American trial, rates of thromboembolic events and vaginal bleeding were higher in the underestimated the benefit of letrozole therapy.10 Similar to 9 tamoxifen group. A combined analysis of these trials showed findings in the anastrozole trials, patients with ER-positive that anastrozole was as effective as tamoxifen in the intent-todisease treated with letrozole had a significantly better retreat (ITT) population, with a decreased risk of thromboemsponse than did patients treated with tamoxifen.11 Letrozole also has been studied in postmenopausal women bolic disease and vaginal bleeding, and significantly prolonged with primary breast cancer who had completed approximately time to disease progression compared with tamoxifen observed 5 years of therapy with tamoxifen.15 Patients were randomin patients with ER-positive disease.2,13 Upon further examination of these data, a clear pattern ized to letrozole 2.5 mg (n = 2575) or placebo (n = 2582) for emerges in patients with ER-positive disease. In the inter5 years. However, because there was a significant disease-free national anastrozole trial showing equivalence between the survival benefit for letrozole compared with placebo at the first agents, receptor status was unknown in more than 50% of interim analysis, the study was concluded after patients had a patients.9 In the North American trial favoring anastrozole, median follow-up of 2.4 years. There were 75 recurrences or nearly 90% of patients were ER positive.8 Thus, patients with new breast cancers in the letrozole group compared with 132 ER-positive disease appear to derive a longer duration of cliniin the placebo group (hazard ratio 0.57; 95% confidence intercal benefit with anastrozole versus tamoxifen therapy. val: 0.43-0.75; P = 0.00008). The estimated 4-year disease-free survival rate was 93% and 87% (P ≤0.001) in the letrozole and Letrozole. Letrozole 2.5 mg once daily was compared with placebo groups, respectively. tamoxifen 20 mg once daily in 907 postmenopausal patients with advanced breast cancer.11 Sixty-five percent of patients Exemestane. Exemestane, the steroidal aromatase inhibitor, had ER-positive or progesterone receptor–positive tumors. is currently undergoing phase III trials. Preliminary results Clinical benefit rates (CR + PR + SD ≥24 weeks) were sigof a small phase II trial comparing exemestane and tamoxinificantly higher in the letrozole group (49%) compared with fen as first-line therapy in 63 postmenopausal patients with the tamoxifen group (38%) (P = 0.001; Table 1). Median metastatic breast cancer are available. Exemestane had an time to progression was significantly longer in the letrozole objective response rate of 42% vs. 16% for tamoxifen. Clinical group compared with the tamoxifen group (9.3 months vs. 6.0 benefit (CR + PR + SD ≥24 weeks) rates were also higher for months, respectively; P = 0.0001).11 Median overall survival in exemestane than tamoxifen (58% vs. 31%). Median time to this trial was 34 months in the letrozole arm and 30 months progression was 8.9 months vs. 5.2 months, respectively.10,12
Clinical Breast Cancer Supplement November 2003
• S85
Aromatase Inhibitors in Breast Cancer Postmenopausal women with invasive breast cancer
Aromatase Inhibitors in the Adjuvant Setting: The ATAC Trial
Surgery radiotherapy chemotherapy Randomization 1:1:1
Anastrozole 1 mg qd + Placebo
Tamoxifen 20 mg qd + Placebo
Anastrozole 1 mg qd + Tamoxifen 20 mg qd
Regular follow-up
Primary trial endpoints
Secondary trial endpoints
• Disease-free survival
• Incidence of contralateral breast cancer
• Safety/tolerability
• Time to distant recurrence • Survival
Taken together, these clinical trials demonstrate that the nonsteroidal aromatase inhibitors should be considered as first-line therapy for postmenopausal women with advanced breast cancer.
Tolerability In general, third-generation aromatase inhibitors are very well tolerated. These newer agents have fewer adverse effects, largely because they are relatively inert compounds. The most common adverse events include hot flashes and gastrointestinal complaints (eg, nausea and vomiting).10 Unlike tamoxifen, these agents, particularly the nonsteroidal aromatase inhibitors (eg, anastrozole, letrozole), lack intrinsic agonist properties. As reported in the first-line therapy trials, there was a consistently lower risk of thromboembolic events and less vaginal bleeding with the aromatase inhibitors than with
$'("#$%)'!$ ( $!!$+ # . !(&!$$% $&($", . ,&' . ,&'+ ( # #(()(&)'#"#$&& $& "$#( ' . "#$&& $&"$#( ' $!! )!&'( ")!( # $&"$# $##(&( $#'+ ( #( %$'("#$%)'!&# '($!$ !!,%&$*#$%&! #*' * '' '(&$ #&%($&-%$' ( *'(&$ #&%($&-# ( *$&)# #$+#'(()' $* #$ "('(( ''
S86 • Clinical Breast Cancer Supplement November 2003
tamoxifen.8,9,11 These findings are of particular importance when considering the use of these novel agents in the adjuvant setting.
Based on their excellent activity as firstand second-line therapies in the setting of advanced disease, third-generation aromatase inhibitors are being evaluated in the adjuvant setting in early breast cancer. The first of these studies to be reported is the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial.2 This randomized, multicenter study compared anastrozole 1 mg daily, tamoxifen 20 mg daily, or daily anastrozole 1 mg and tamoxifen 20 mg in a 1:1:1 combination (Figure 2). Eligible patients were postmenopausal, had histologically documented invasive breast cancer that was operable, had completed primary surgery and chemotherapy, and were candidates for adjuvant hormonal therapy (Table 2).
Efficacy The primary endpoints of the trial were disease-free survival and safety and tolerability.2 Disease-free survival was defined as the time to the earliest occurrence of local or distant recurrence, new primary breast cancer, or death from any cause. Secondary endpoints included time to recurrence, incidence of new contralateral primary breast tumors, distant recurrence, and overall survival. Patients were assessed for efficacy and safety at study entry, at 3 months, at 6 months, and every 6 months thereafter for up to 5 years, then annually for up to 10 years. The primary endpoint of disease-free survival was used to determine study sample size.2 For noninferiority to be concluded between anastrozole and tamoxifen, 352 events per group were needed to achieve > 90% power. The main data analysis took place after a total of 1056 first events. The first results in 9366 patients (anastrozole, n = 3125; tamoxifen, n = 3116; combination, n = 3125) were reported in June 2002, with a median follow-up at approximately 33 months. An updated analysis of the study was performed at a 47month follow-up (Figure 3) at which the number of first events increased from 1079 to 1373.16 In ER-positive patients, who account for 84% of all patients, the number of first events increased from 766 to 991 between the 33-month and 47-month analyses. First events that occurred in the ITT and ER-positive populations are summarized in Table 3. In the updated ITT analysis focusing on the anastrozole and tamoxifen arms only, the time-to-first-event curves continue to diverge (Figure 4). The absolute differences between treatments in the time to first event were 1.5% at the 3-year follow-up and 2.4% at the 4-year follow-up.16 Similarly, the absolute differences between treatments in the time to recurrence were 1.7% and 2.3% at the 3- and 4-year followup periods, respectively. Likewise, in the ER-positive
Aman U. Buzdar patients, consistent results were observed. At the 3- and 4-year follow-up periods, the absolute differences in the time to first event (1.7% vs. 2.9%, respectively) and time to recurrence (1.8% and 2.6%, respectively) increased over time, with proportional hazard reductions of 17% for the risk of a first event and 22% for the risk of a recurrence with anastrozole over tamoxifen therapy. It is of note that the tamoxifen event rate, when adjusted for nodal status, was nearly identical in both the ATAC2 and Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)1 trials, suggesting that the improved efficacy observed with anastrozole was due to enhanced antitumor activity rather than a suboptimal performance of tamoxifen.2
ITT Population Anastrozole (n = 3125)
Tamoxifen (n = 3116)
Anastrozole (n = 2617)
Tamoxifen (n = 2598)
413 (13.2%)
472 (15.1%)
290 (11.1%)
345 (13.3%)
84 (2.7%)
101 (3.2%)
48 (1.8%)
62 (2.4%)
195 (6.2%)
222 (7.1%)
133 (5.1%)
158 (6.1%)
20 (0.6%)
35 (1.1%)
17 (0.6%)
31 (1.2%)
Event
Invasive Ductal carcinoma in situ
5 (0.2%)
5 (0.2%)
3 (0.1%)
4 (0.2%)
109 (3.5%)
109 (3.5%)
88 (3.4%)
90 (3.5%)
# !$ ! # ! " Abbreviations: ATAC = Arimidex, Tamoxifen Alone or in Combination; ER = estrogen receptor; ITT = intent to treat
Safety and Tolerability Much of the available data suggest that, compared with tamoxifen, anastrozole therapy results in significantly fewer postmenopausal symptoms, including hot flashes, vaginal discharge, vaginal bleeding, thromboembolic events, ischemic cerebrovascular events, and endometrial cancer.2 This can be partly explained by the lack of agonist activity of aromatase inhibitors. Symptoms sometimes characterized as minor, such as vaginal bleeding, often result in a cascade of potentially avoidable events. In particular, a vaginal bleeding episode in a postmenopausal woman often leads to a full workup, including ultrasonography, dilation and curettage, and biopsy to diagnostically rule out endometrial cancer. Reductions in
100
90
80
70 60 50
40 30 20 10 0
1
2
ER-Positive Population
3
4
5
the occurrence of these events with anastrozole use are likely to avoid unnecessary anxiety and health-care costs. A second concern is the risk of endometrial cancer with long-term use of tamoxifen, and it is of substantial importance that a nearly 70% reduction in the incidence of endometrial carcinoma was noted in the anastrozole group in the ATAC trial.16 Additionally, the incidence of other primary cancers (eg, colorectal, head and neck, lung, melanoma, ovary, and skin) was similar across treatment groups. Last, substantial risk reductions were associated with anastrozole over treatment with tamoxifen alone with respect to ischemic events (53%; odds ratio 0.47; P = 0.0006) and thromboembolic events (42%; odds ratio 0.58; P = 0.0006), respectively. Based on the findings in the ATAC trial, only two events favored tamoxifen over anastrozole treatment: joint stiffness and musculoskeletal discomfort, which appear to be a class effect of the aromatase inhibitors, and an increased risk of bone-related fractures.2 The incidence of hip fractures appears to be similar across the two treatments; rib and spinal fractures were less common in patients treated with tamoxifen.2 Fractures may be the result of a dual effect: loss of the protective partial-agonist effect of tamoxifen on bone and estrogen deprivation caused by aromatase inhibitors. Patients should be informed of these risks, with physicians assessing the need for a baseline bone density test and appropriate follow-up, intervention, or both. Overall, nearly 90% of patients adhered to therapy, with significantly fewer patients in the anastrozole group discontinuing treatment due to an adverse event (anastrozole 7.8% vs. tamoxifen 11.1% vs. combination 10.9%; P < 0.0001).16 The fact that significantly fewer adverse events occurred in patients treated with anastrozole is of particular importance for its potential long-term use in the adjuvant setting.2
Conclusion Aromatase inhibitors are clearly beneficial in postmenopausal women with advanced breast cancer, particularly those with ER-positive tumors. Based on the available data to date, there is also a choice of adjuvant endocrine therapy for post-
Clinical Breast Cancer Supplement November 2003
• S87
Aromatase Inhibitors in Breast Cancer $ " ! ! # $ $ ! 20
AN vs TAM
HR
95% CI
value
0.86
0.76-0.99
0.030
15 Anastrozole Tamoxifen 10
5
0
6
12
18
24
Absolute Difference 1.5 %
Absolute Difference 2.4 %
30
42
36
48
54
1489 1452
726 703
Number of Patients at Risk AN 3125 TAM 3116
2997 2991
2861 2821
2634 2577
! ! !! $ "% !!! " ! ! $ " ! # Abbreviations: AN = anastrozole; CI = confidence interval; HR = hazard ratio; TAM = tamoxifen
menopausal women with hormone-responsive tumors. The initial findings from the ATAC trial, which were consistently supported in the updated analysis, demonstrate a significant improvement in disease-free survival and improved safety and tolerability with anastrozole compared with tamoxifen.2 Future and ongoing studies will further define the role of the aromatase inhibitors for adjuvant therapy of early breast cancer and in women at increased risk of breast cancer.
References
1. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451-1467. 2. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:2131-2139.
S88 • Clinical Breast Cancer Supplement November 2003
3. Geisler J, King N, Dowsett M, et al. Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer 1996; 74:1286-1291. 4. Buzdar AU, Jonat W, Howell A, et al, for the Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer 1998; 83:1142-1152. 5. Buzdar A, Douma J, Davidson N, et al. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 2001; 19:3357-3366. 6. Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998; 16:453-461. 7. Kaufmann M, Bajetta E, Dirix LY, et al, for the Exemestane Study Group. 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. J Clin Oncol 2000; 18:1399-1411. 8. Nabholtz JM, Buzdar A, Pollak M, et al, for the Arimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758-3767. 9. Bonneterre J, Thurlimann B, Robertson JFR, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000; 18:3748-3757. 10. Assikis VJ, Buzdar A. Recent advances in aromatase inhibitor therapy for breast cancer. Semin Oncol 2002; 29 (suppl 11):120-128. 11. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596-2606. 12. Paridaens R, Dirix LY, Beex L, et al. Exemestane (Aromasin) is active and well tolerated as first-line hormonal therapy (HT) of metastatic breast cancer (MBC) patients (Pts): results of a randomized phase II trial. Proc Am Soc Clin Oncol 2000; 19:83a (Abstract #316). 13. Buzdar A, Nabholtz JM, Robertson JF, et al. Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer (Abc) in postmenopausal (Pm) women—combined analysis from two identically designed multicenter trials. Proc Am Soc Clin Oncol 2000; 19:154a (Abstract #609D). 14. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21:21012109. 15. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for earlystage breast cancer. N Engl J Med 2003;349:1793-1802. 16. Buzdar A. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial in postmenopausal women with early breast cancer–updated efficacy results based on a medial follow-up of 47 months (abstract). Breast Cancer Res Treatment 2003; 77:295. 17. Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98:1779-1781.