Aromatase Inhibitors in Postmenopausal Breast Cancer Patients

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Original Article

Alyssa G. Rieber, MD, and Richard L. Theriault, DO, MBA, Houston, Texas

Key Words the 1970s. It decreases estrogen’s effect on breast cancer Breast cancer, aromatase inhibitor, postmenopausal cells by competing with estrogen for binding with the receptor. It is well tolerated but has associated side effects Abstract of hot flashes, vaginal dryness, and increased risk of throm- Aromatase inhibitors (AIs) have greatly enriched the treatment of boembolic events and uterine cancer.2 Its benefit in the hormone receptor-positive breast cancer in postmenopausal pa- treatment of hormone receptor-positive breast cancer has tients. Before the introduction of the well-tolerated third-generation been well established. The Early Breast Cancer Trialists’ AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the Group reviewed 55 randomized trials of 37,000 women superiority of AIs compared with tamoxifen in adjuvant breast can- treated with tamoxifen in the adjuvant setting. In the cer treatment, as well as their benefit in metastatic breast cancer. women with estrogen receptor (ER)-positive disease who NCCN guidelines recommendations for their use are based on the took tamoxifen for 5 years, the decrease in disease recur- evidence provided by these clinical trials. This discussion reviews the rence was 50% and decrease in mortality was 26%.3 evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast Recent trials have shown that the aromatase inhibitors cancer patients. (JNCCN 2005;3:309–314) are even more effective than tamoxifen in reducing the risks of breast cancer recurrence.

The concept of hormone therapy in breast cancer dates 1 from 1896 when Beatson reported oophorectomy caus- Development of Aromatase Inhibitors ing the regression of advanced breast cancer. Much work has been done in the interim, with endocrine therapies Aromatase is part of the cytochrome P450-dependent becoming a mainstay in the treatment of breast cancer. enzyme family and a product of the CYP19 gene. Its ex- This discussion focuses on the treatment of hormone pression in the placenta of pregnant women and granu- receptor-positive breast cancer with aromatase inhibitors losa cells of ovarian follicles in premenopausal women is (AIs) in postmenopausal women. To establish their place regulated by gonadotropin stimulation. Other areas of in the treatment of breast cancer, they first were com- expression include subcutaneous fat, brain, muscle, liver, pared against the standard of care, tamoxifen. and both normal and malignant breast tissue. In post- Tamoxifen is a selective estrogen receptor modulator menopausal women, peripheral aromatase produces estro- (SERM) that has been used to treat breast cancer since gen in subcutaneous fat. AIs block the enzymatic pathway of aromatase and therefore decrease the level of estrogen production and total circulating estrogen. Aminoglutethimide is a first-generation aromatase From the Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. inhibitor that became available for clinical use in the Submitted February 11, 2005; accepted for publication March 31, 2005. 1970s. It is a nonselective aromatase inhibitor with side The authors have no financial interest, arrangement, or affiliation with the manufacturers of any products discussed in the article or their effects of adrenal insufficiency, rash, nausea, somnolence, competitors. and blood dyscrasias. Second-generation aromatase in- Correspondence: Richard L. Theriault, DO, MBA, Professor of Medicine, Department of Breast Medical Oncology, The University of Texas M.D. hibitors formestane and fadrozole have limited use be- Anderson Cancer Center, 1515 Holcombe Blvd., Box 424, Houston, TX cause of extensive first-pass hepatic metabolism and 77030. E-mail: [email protected] adrenal mineralocorticoid suppression, respectively.4

Rieber and Theriault

Because of these negative clinical effects, researchers Table 1 Classification of Aromatase Inhibitors needed to develop more selective aromatase inhibitors. Type 1 Type 2 Third-generation aromatase inhibitors were (Steroidal (Nonsteroidal introduced for clinical use in the 1990s. Their classi- Generation Inactivator) Inhibitor) fication, along with the classification of second- First None Aminoglutethimide generation AIs is according to mechanism of action. Second Formestane Fadrozole Type 1 inhibitors, steroidal enzyme inhibitors, bind Rogletimide irreversibly to the androstenedione binding site. The Third Exemestane Anastrazole effects of type 2, nonsteroidal inhibitors on aromatase Letrozole enzyme are reversible. The nonsteroidal enzyme in- Vorozole hibitors bind to the heme component of aromatase via a basic nitrogen group (Figure 1). All third- generation AIs are highly selective and have good oral group versus 7.0 months in tamoxifen group (P = .103). bioavailability. Exemestane is a type 1 inhibitor, Tumor response was equivalent as well (29% vs. 27.1%; and anastrozole and letrozole are type 2 inhibitors P = .1129).6 However, in the North American trial, (Table 1). in which the percentage of patients with ER-positive disease was greater than in the TARGET trial (90% vs. less than 50%), the results did have statistical dif- Advanced Disease ferences. An unplanned retrospective analysis was per- The clinical benefit of the third-generation AIs was formed to further evaluate anastrozole versus tamoxifen shown first in studies that compared AIs with mege- in patients with confirmed ER-positive disease. In the strol acetate for second-line hormonal therapy after North American group, the median time to progres- tamoxifen in metastatic breast cancer. These trials sion was 11.1 months for anastrozole versus 5.6 months showed slight clinical benefit and, most importantly, for tamoxifen (P = .005), and the overall response rate an improved side effect profile compared with mege- was equivalent (21% vs. 17%). Clinical benefit, de- strol acetate. The AIs did not induce the weight gain fined as complete or partial response and stable disease seen with megestrol acetate and were relatively well for 24 weeks or more, was significantly greater in the tolerated.5 anastrazole group (59% vs. 46%; P = .0098).7 The efficacy of AIs compared with tamoxifen as The International Letrozole Breast Cancer Group first-line therapy in advanced breast disease was ad- enrolled 916 patients with ER-positive advanced breast dressed with randomized, multicenter, double-blind cancer in a randomized trial of letrozole versus tamox- studies in the 1990s. Two trials in North America ifen. The initial report showed letrozole to be superior (North American trial) and Europe (TARGET trial) to tamoxifen in median time to progression (41 vs. 26 of anastrozole versus tamoxifen were designed for com- weeks), overall response rate (30% vs. 20%; P = .0006), bined analysis, and they showed an equivalent me- and clinical benefit (49% vs. 38%; P = .001).8 Follow- dian time to progression: 8.5 months in anastrozole up analysis at 32 months showed overall survival to be 34 versus 30 months (P = .53) and time to chemotherapy (total duration of endocrine therapy based on initial treatment arm) to be 16.3 versus 9.3 months for the letrozole and tamoxifen groups, respectively (P = .005).9 Trials of exemestane versus tamoxifen as first-line therapy of advanced breast cancer are ongoing. A phase II trial from the EORTC showed response rates of 41% versus 17% and clinical benefit of 57% versus 42%.10 This was a small trial of 120 patients that led to a phase III trial. These phase III results were pre- Figure 1 Mechanism of action of aromatase inhibitors. sented at the American Society of Clinical Oncology

Aromatase Inhibitor Therapy for Breast Cancer

(ASCO) annual meeting in 2004. The study included Follow-up disease-free survival data with a me- 382 evaluable patients with a median follow-up time dian follow-up time of 47 months continued to signif- of 29 months. Exemestane showed a superior overall icantly favor anastrozole over tamoxifen alone (86.9% response rate (46% vs. 31%; P = .005) and clinical vs. 84.5%; HR, 0.86; CI, 0.76–0.99; P = .03). benefit rate (66% vs. 49%) than tamoxifen. Contralateral breast cancers also were decreased in Progression-free survival trended towards benefit with the anastrozole group with hormone receptor-positive exemestane (9.9 months vs. 5.8 months) but did not disease (odds ratio, 0.56; CI, 0.32–0.98; P = .042). reach significance.11 Safety analysis confirmed the initial observations as These studies showed the equivalence or superi- well.14 Five-year data were published recently, with ority of AIs versus tamoxifen in advanced disease. The anastrozole continuing to prolong disease-free survival National Comprehensive Cancer Network (NCCN) (HR, 0.87; CI, 0.78–0.97; P = .01) and time to disease guidelines recommend AIs or antiestrogens as first- recurrence (HR, 0.79; CI, 0.70–0.90; P = .0005). The line therapy in postmenopausal breast cancer patients number of distant metastases was lower in the anas- with hormone receptor-positive metastatic disease.12 trozole group (HR, 0.86; CI, 0.74–0.99; P = .04), as was the number of contralateral breast cancers (42% re- Adjuvant Treatment duction; CI, 12%–62%; P = .01). Overall survival was The Early Breast Cancer Trialists’ Collaborative Group not statistically significantly different (HR, 0.97; CI, analyzed data from 55 trials of adjuvant tamoxifen 0.85-1.12; P = .7).15 This study established anastro- versus placebo among women with early breast can- zole as the preferred initial adjuvant therapy in post- cer. In patients with ER-positive breast cancer taking menopausal women with hormone receptor-positive tamoxifen, the 5-year recurrence reduction was 50% breast cancer, and longer-term follow up has contin- and decrease in mortality was 26%.3 With this dra- ued to support this.16 matic impact on the treatment of breast cancer, The next group of patients to be evaluated was tamoxifen became the standard of care for adjuvant the patient population that had completed the rec- endocrine therapy. ommended 5 years of tamoxifen therapy. The National The first reported adjuvant trial of a third-gener- Surgical Adjuvant Breast and Bowel Project B14 trial ation AI was the Arimidex, Tamoxifen, Alone or in showed significantly superior disease-free survival in Combination (ATAC) study.13 In this study, 9,366 patients who underwent 5 years of tamoxifen therapy postmenopausal patients with ER-positive invasive compared with those who continued tamoxifen ther- breast cancers were treated with primary surgery and apy for more than 5 years (82% vs. 78%; P = .03), and chemotherapy (when indicated) and then random- overall survival trend was towards a benefit for 5 years ized to recived anastrozole, tamoxifen, or a combina- of therapy (94% vs. 91%; P = .07).17 With the addition of both. The first results were published in 2002 tion of AIs to the endocrine therapy of breast cancer, with 33.3 months median follow-up time. Disease- a trial was begun to compare 5 years of tamoxifen with free survival favored anastrozole over tamoxifen alone, the sequential addition AI therapy or placebo. with 3-year survival rates of 89.4% versus 87.4% (haz- The MA17 trial was a double-blind, placebo-con- ard ratio [HR], 0.83; 95% confidence interval [CI], trolled, multicenter trial comparing letrozole with 0.71–0.96; P = .013). Disease-free survival in the com- placebo in patients who had completed 4.5 to 6 years bination group (87.2) was not statistically different of tamoxifen therapy.18 At study entry, 5,187 women from that in the tamoxifen alone group (HR, 1.02; who had completed 4.5 to 6 years of tamoxifen and CI, 0.89–1.18; P = .8). Anastrozole also significantly were disease free at that time were randomized to reduced the rate of contralateral breast cancers com- receive letrozole 2.5 mg daily or placebo. At 4-year pared with tamoxifen (odds ratio, 0.42; CI, 0.22–0.79; follow-up, disease-free survival was 93% versus 87% P = .007). Anastrozole-treated patients experienced (P ഛ.001) for the letrozole and placebo groups, re- fewer cerebrovascular events, thromboembolic events, spectively. Overall survival was not statistically sig- hot flushes, and endometrial cancer than the tamox- nificantly different. The letrozole group experienced ifen-treated patients. Tamoxifen-treated patients had more hot flashes, arthralgias, myalgias, and arthritis. fewer musculoskeletal disorders and fractures than the More women in the letrozole group were diagnosed anastrozole group.13 with osteoporosis (5.8% vs. 4.5%; P = .07), but the rate

Rieber and Theriault

of fracture was not statistically significantly different. Neoadjuvant Treatment Because of these results, the study was closed early. In 2001, a randomized double-blind multicenter study Letrozole is recommended for 5 years after tamoxifen was published comparing letrozole with tamoxifen in therapy. Further studies will further clarify the bene- the neoadjuvant setting. Three hundred thirty-seven fit of AIs after tamoxifen and the appropriate duration postmenopausal women with untreated hormone re- of therapy. ceptor-positive breast cancer were treated with letro- Other studies have explored the benefit of chang- zole 2.5 mg daily or tamoxifen 20 mg daily for 4 ing endocrine therapy to AIs after the patient has be- months. None of the patients was eligible for breast- gun tamoxifen therapy. The Intergroup Exemestane conserving surgical therapy at diagnosis, and 14% of Study (IES) evaluated switching to exemestane after the cancers were considered inoperable. The overall 2 to 3 years of tamoxifen adjuvant therapy in post- objective response rate (determined by clinical pal- menopausal, hormone receptor-positive breast cancer pation) was 55% in the letrozole group and 36% in the patients. In this study, 4,742 patients who had taken tamoxifen group (P < .001). Breast ultrasound response tamoxifen for 2 to 3 years were randomized to con- was 35% versus 25% (P = .042); mammographic re- tinue tamoxifen (20 mg daily) or change to exemes- sponse was 34% versus 16% (P < .001); and the rate tane (25 mg daily) to complete a total of 5 years of breast-conserving surgery was 45% versus 35% endocrine therapy. After a median follow-up time of (P = .022).20 30.6 months, the exemestane group had improved dis- Another study evaluated neoadjuvant exemes- ease-free survival (HR, 0.68; CI, 0.56–0.82; P < .0001). tane versus tamoxifen in postmenopausal ER-positive This corresponded to an absolute risk reduction of breast cancer patients. Seventy-three patients were 4.7% (CI, 2.6–6.8) at 3 years. Overall survival was treated with exemestane 25 mg daily or tamoxifen 20 not statistically significantly different at 3 years (HR, mg daily for 3 months and evaluated for response. 0.88; CI, 0.67–1.16; P = .37). Exemestane was also Clinical response was higher in the exemestane group found to decrease risk of contralateral breast cancers (88.6% vs. 57.3%; P < .05), and the rate of breast- (HR, 0.44; CI, 0.2–0.98; P = .04).19 Based on this study, conserving surgery was higher in the exemestane group 21 the current NCCN recommendation is to consider (38.7% vs. 10.8%; P < .05). switching to exemestane for patients who have com- A recently presented study evaluated chemotherapy versus endocrine therapy in the neoadjuvant set- pleted 2 to 3 years of tamoxifen.12 ting. In this study, 146 women with hormone The Italian trial (ITA) was an open-label prospec- receptor-positive breast cancer were randomized to tive trial of 426 postmenopausal women with hor- chemotherapy with doxorubicin and paclitaxel for four mone receptor-positive breast cancer who had cycles or 3 months of anastrozole (1 mg daily) or ex- completed 2 to 3 years of tamoxifen therapy. They emestane (25 mg daily). The tumors were AJCC stage were randomized to receive anastrozole or tamoxifen T2N1-2, T3N0-1, or T4N0M0 (excluding inflamma- to complete 5 years of endocrine therapy. The findings tory).22 The overall objective response rate, determined were consistent with anastrozole decreasing the risk of by clinical palpation and mammography, was not sta- 16 recurrent disease (HR, 0.36; CI, 0.17-0.75; P = .006). tistically significantly different (chemotherapy, 76% The current NCCN guidelines recommend the and 61.9%; anastrozole, 75.6% and 62.1%; and ex- following therapeutic algorithm for postmenopausal emestane, 81.5% and 71%). The rate of breast-con- women with hormone receptor-positive breast cancer:12 serving surgical therapy trended toward benefit of • Initial adjuvant endocrine treatment endocrine therapy (chemotherapy, 23.9%; anastrozole, • Anastrozole 1 mg daily for 5 years 33.3%; and exemestane, 34%; P = .058). Endocrine • Treatment with tamoxifen for 2 to 3 years, discuss therapy was well tolerated with less toxicity than • Exemestane 25 mg daily to complete 5 years chemotherapy.23 These trials show the benefit of AIs total therapy in the neoadjuvant setting. This option provides an al- • Anastrozole 1 mg daily to complete 5 years ternative to chemotherapy for patients opposed to total therapy chemotherapy or those with comorbidities. The • Treatment with tamoxifen for 4.5 to 6 years, discuss NCCN guidelines state that hormonal therapy may be • Letrozole 2.5 mg daily for 5 years considered for treatment in the preoperative setting

Aromatase Inhibitor Therapy for Breast Cancer for postmenopausal women with hormone receptor- to evaluate the length of therapy in the adjuvant set- positive breast cancer. The preferred hormonal ther- ting, comparison of the efficacy and toxicity of AIs, and apy is an aromatase inhibitor.12 their role in chemoprevention for breast disease (two studies are pending).25 In all, aromatase inhibitors have dramatically impacted the treatment of hormone re- Comparison of Aromatase Inhibitors ceptor-positive breast cancer in postmenopausal With many studies demonstrating the superiority of the women and will continue to be an asset to clinicians three available AIs compared with tamoxifen, the is- in the treatment of disease. sue arises as to which of the AIs is superior. Are they to be used interchangeably, and can the data from one study be extrapolated to the other AIs? One compar- References ison study was an open randomized trial comparing 1. Beatson GT. 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