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2620 Vol. 7, 2620 –2635, September 2001 Clinical Cancer Research Review Advances in Aromatase Inhibition: Clinical Efficacy and Tolerability in the Treatment of Breast Cancer Aman Buzdar1 and Anthony Howell Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University of Texas, Houston, Texas 77030 [A. B.], and Cancer Research Campaign Department of Medical Oncology, Christie Cancer Research Campaign Research Centre, Christie Hospital National Health Services Trust, Manchester, United Kingdom [A. H.] Introduction The successful management of breast cancer remains a major challenge to surgeons and oncologists in the 21st century. Although the incidence of breast cancer varies throughout the world, the disease is universally perceived to be a major cause of morbidity and mortality in both pre- and postmenopausal women. It has long been established that estrogen is the major hormone involved in the biology of breast cancer (1). Endocrine agents have therefore been designed to affect the supply of estrogens to the breast tumor, principally by blockade of estrogen activity at the receptor level or by inhibition of estrogen production (although the widely used antiestrogen, tamoxifen, is known to have additional modes of action, such as via production of the inhibitory growth factor transforming growth factor  (2, 3) and suppression of insulin-like growth factor 1 (4), a potent mitogen for breast cancer. Drug resistance, however, remains a significant problem in breast cancer treatment, and this has led to the development of a variety of endocrine agents to extend the treatment options for breast cancer patients with hormone-sensitive disease. The success of the approach to use different endocrine therapies sequentially is made evident by the fact that 25% of patients with advanced breast cancer who eventually progress after an initial response on primary treatment are known to respond to second-line therapy with another endocrine agent (5). In a recent study, ⬃40% of patients with advanced breast cancer failing after an initial response to tamoxifen gained clinical benefit (clinical benefit ⫽ CR2 ⫹ PR ⫹ SD ⱖ 24 weeks) from the second-line use of a second endocrine therapy (6). Over the past 30 years, the antiestrogen, tamoxifen, has Received 9/7/00; revised 3/30/01; accepted 6/1/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University of Texas, Houston, TX 77030. 2 The abbreviations used are: CR, complete response; PR, partial response; SD, stable disease; TTP, time to progression; OR, objective response rate; TTF, time to treatment failure; UICC, Union International Contre Cancer; HR, hazard ratio; ER, estrogen receptor; PgR, progesterone receptor; CI, confidence interval; ATAC, Arimidex, tamoxifen, alone or in combination; ABCSG, Austrian Breast Cancer Study Group. been the most widely used endocrine drug for the management of all stages of breast cancer in women with estrogen-dependent tumors, irrespective of their age and menopausal status (7–9), and, until recently, it has maintained an unrivalled position as the standard first-line endocrine therapy for postmenopausal women with advanced breast cancer. Aromatase inhibitors are endocrine agents which have a different mode of action against breast tumors in postmenopausal women from that of tamoxifen. The first clinically available aromatase inhibitor, aminoglutethimide, was introduced for the second-line treatment of advanced breast cancer in the late 1970s (10). But despite proven efficacy in this setting, its widespread use was limited by its overall toxicity and its lack of selectivity for the aromatase enzyme, which necessitated concomitant corticosteroid supplementation (11). This led to the search for novel, more effective, and less toxic aromatase inhibitors. As a result, several aromatase inhibitors with a high degree of selectivity for aromatase and improved tolerability have become clinically available for the treatment of postmenopausal women with advanced breast cancer: anastrozole (1 mg once daily); letrozole (2.5 mg once daily); fadrozole (1 mg twice daily; available in Japan only); formestane (250 mg i.m. every 2 weeks); and exemestane (25 mg once daily; Fig. 1; Refs. 12–22). It is the aim of this review to evaluate the clinical efficacy and tolerability of these latest additions to this class of drugs in the management of advanced breast cancer in postmenopausal women and to discuss their potential for use in the adjuvant treatment of early disease. Pharmacology of Aromatase Inhibitors In postmenopausal women, ovarian estrogen production diminishes with age. In these women, estrogen concentrations are maintained primarily via aromatase, a cytochrome-p450 enzyme complex which acts at the final step in the estrogensynthesis pathway and catalyzes the production of the estrogens, estrone and estradiol, by extraglandular conversion from the androgens, androstenedione, and testosterone, respectively (Fig. 2). It is knowledge of this peripheral route of estrogen supply in postmenopausal women that has led to the development of the aromatase inhibitors. These drugs act by suppression of the supply of endogenous estrogens in fat, liver, and muscle cells and in breast tumor tissue itself. They can be divided into two classes: steroidal and nonsteroidal drugs (23). The steroidal class (type I) comprises primarily formestane and exemestane, and the nonsteroidal class (type II) comprises primarily the imide, aminoglutethimide; the imidazole, fadrozole; and the triazoles, anastrozole and letrozole. A third nonsteroidal triazole, vorozole, has recently been withdrawn from clinical development. Method of Administration. The newer nonsteroidal drugs, anastrozole and letrozole, are well absorbed after oral administration, with long terminal half-lives, allowing for oncedaily dosing (14 –16). In contrast, the first steroidal drug to Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2621 Fig. 1 Chemical structures of all aromatase inhibitors under review. Fig. 2 Enzyme pathway for estrogen synthesis from androgens via aromatase inhibitors. become clinically available, formestane (250 mg i.m. every 2 weeks), is subject to high first-pass metabolism when given p.o., and has a relatively short terminal half-life (⬃2 h), and consequently has to be administered by i.m. injection every 2 weeks (18, 24). Exemestane, the other steroidal drug, is p.o. bioavailable and has a terminal half-life of ⬃24 h during chronic treatment (21), allowing once-daily therapy at a dose of 25 mg of drug (25, 26). Mechanism of Action. Steroidal and nonsteroidal aromatase inhibitors differ in their modes of interaction with, and their inactivation of, the aromatase enzyme. Steroidal inhibitors compete with the endogenous substrates, androstenedione and testosterone, for the active site of the enzyme, where they act as false substrates and are processed to intermediates that bind irreversibly to the active site, causing irreversible enzyme inhibition. Nonsteroidal inhibitors also compete with the endogenous substrates for access to the active site, where they then form a coordinate bond to the heme iron atom. Therefore, they effectively exclude both the natural substrate and oxygen from the enzyme. The coordinate bonding is strong but reversible, so that enzyme activity can recover if the inhibitor is removed; but inhibition is sustained whenever the inhibitor is present. Al- Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. 2622 Aromatase Inhibition in Breast Cancer Treatment though both classes of aromatase inhibitor lead to potent suppression of aromatase, the enzyme is capable of rapid regeneration, and so it is doubtful whether or not the type of inhibition (i.e., reversible or irreversible) is of any clinical relevance. There are currently no clinical data that compare the relative efficacy of each type of agent. Their different modes of action, however, allow for sequential use in patients with advanced breast cancer, as described later. Selectivity. The degree of selectivity of an aromatase inhibitor for the aromatase enzyme has a bearing on both the ease of use and the tolerability profile of the drug. For instance, the lack of selectivity of the first-generation aromatase inhibitor for aromatase, aminoglutethimide, led to concomitant suppression of the important corticosteroids, aldosterone and cortisol. As a result, in clinical use, it became necessary to coadminister a corticosteroid, such as hydrocortisone, as replacement therapy (11). Although the second-generation aromatase inhibitor, fadrozole, was shown to be more potent and selective (23) than aminoglutethimide, it nevertheless demonstrated a lack of selectivity through its effect on 11-deoxycorticosterone and aldosterone concentrations as well as on sodium and potassium levels in animals (11, 27–30). The third-generation aromatase inhibitor, anastrozole, has a high degree of selectivity for aromatase in clinical pharmacology studies, with no significant effects being observed on either cortisol or aldosterone secretion at up to 10 times the daily recommended dose after 28 days of exposure (31, 32) and also when given for up to 3 months (33). Letrozole showed a similar degree of enzyme selectivity after an exposure period of 28 days, (34, 35) although in a study evaluating the dosing of letrozole 0.5 mg over a period of 12 weeks, cortisol levels were reduced significantly at this dose after 2 months (36) while remaining within the limits of normality (37, 38). Additionally, a more recent study has shown significant reductions in adrenocorticorticotropic hormone-stimulated cortisol (P ⫽ 0.015) and aldosterone (P ⫽ 0.04) concentrations after a 3-month exposure to letrozole at the clinical dose of 2.5 mg daily (39). Vorozole is also selective for the aromatase enzyme, as seen from studies of 2.5 and 5 mg doses once daily, which reported no effect on adrenal steroidogenesis (40, 41). However, in one study at the 5-mg daily dose, vorozole led to a reduction in cortisol, the clinical relevance of which was uncertain (42). The higher selectivity of anastrozole, letrozole, and vorozole for aromatase leads to improved tolerability, compared with earlier drugs of this class, through an overall lack of adverse effect on steroidogenesis. In the case of the steroidal aromatase inhibitors, both formestane (43– 45) and exemestane (26, 46) are selective for aromatase and do not affect either cortisol or aldosterone concentrations adversely. The available data on selectivity confirm that all of the aromatase inhibitors developed since aminoglutethimide first became clinically available are far more selective than the prototype compound. More recent data from indirect clinical pharmacology studies, however, do show variations between the different aromatase inhibitors. For anastrozole and letrozole, there seem to be differences in overall selectivity that, although not seen after short-term administration, do become apparent after longer-term exposure, i.e., up to 3 months. The clinical relevance of such changes is not yet clear; however, although there may not be any clinical detriment in the metastatic setting, it would be important to monitor closely for the potential impact in the adjuvant setting, where these compounds are likely to be administered for up to 5 years, and where tolerability assumes greater importance in a patient who otherwise may be “cured” of disease. Estrogen Suppression and Aromatase Inhibition. Both steroidal and nonsteroidal aromatase inhibitors result in a significant decrease in serum estrogen concentrations. Aminoglutethimide was the first nonsteroidal aromatase inhibitor to demonstrate a high level of aromatase inhibition, but this was not accompanied by a reduction in estrogen concentrations comparable with that now seen with the third-generation nonsteroidal aromatase inhibitors (23). An increase in potency was found with the second-generation drug, fadrozole (22), but, again in comparison, the newer-generation triazole drugs, anastrozole and letrozole, both produce a much greater suppression of estrogens, to the limits of detection of current assays, and have demonstrated a high degree of consistency between the inhibition of whole-body aromatase activity and estrogen suppression (16, 18, 23, 47). Recent data have been reported from a small, double-blind, randomized, cross-over study in 12 postmenopausal women with advanced breast cancer, comparing plasma estrogen suppression by letrozole (2.5 mg daily) and anastrozole (1 mg daily; 48). This study showed that letrozole led to significantly greater suppression of E1 (P ⫽ 0.019) and E1S (P ⫽ 0.0037), but not of E2, which is widely considered to be the most important estrogen in the etiology of breast cancer. When inhibition of wholebody aromatase was examined (49), it was shown that letrozole (⬎99.1%) achieved a greater inhibition of aromatase than did anastrozole (mean, 96.9%). No statistical analyses of these data have been presented to date, and the clinical relevance of such differences between drugs of this class in their effect upon aromatase remains questionable. The injectable steroidal aromatase inhibitor, formestane, also suppresses estrogen concentrations significantly, but to a lesser extent than anastrozole (50). Formestane is associated with inconsistent suppression of serum estradiol (50, 51), whereby estradiol levels begin to rise between the twice-weekly i.m. doses. This was shown in a small, randomized, comparative study, in which formestane (250 mg i.m. every 2 weeks; n ⫽ 31) was compared with the nonsteroidal aromatase inhibitor, anastrozole (1 mg once daily; n ⫽ 29), over 4 weeks in postmenopausal women with advanced breast cancer (50). More effective, reliable and consistent estradiol suppression was found with anastrozole than with formestane at the usual therapeutic doses (79% versus 58% reduction in estradiol levels, respectively; P ⫽ 0.0001). Estrone and estrone sulfate levels were also significantly suppressed to a greater extent by anastrozole compared with formestane (estrone, 85% versus 67%, P ⫽ 0.0043; estrone sulfate, 92% versus 67%, P ⫽ 0.0007; respectively; Ref. 50). Recently available results indicate that the oral steroidal aromatase inhibitor, exemestane, at daily doses of 10 –25 mg, suppresses estrogen concentrations to 6 –15% of pretreatment levels, showing more pronounced activity than formestane and comparable activity with that of the clinically available, nonsteroidal aromatase inhibitors, anastrozole and letrozole (52, 53). Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2623 Table 1 Efficacy results from Phase III second-line trials of anastrozole versus megestrol acetate (MA) in postmenopausal women with advanced breast cancer (6- and 31-months’ follow-up) European54 Parameter OR ⫽ CR ⫹ PR (%) Clinical benefit (%) Median TTP (mo.) Median survival 2-yr survival rate (%) a b North American55 Combined (6 mo)58 Combined (31 mo)6 Anastrozole 1 mg o.d. (n ⫽ 135) MA 40 mg q.i.d. (n ⫽ 118) Anastrozole 1 mg o.d. (n ⫽ 128) MA 40 mg q.i.d. (n ⫽ 130) Anastrozole 1 mg o.d. (n ⫽ 263) MA 40 mg q.i.d. (n ⫽ 253) Anastrozole 1 mg o.d. (n ⫽ 263) MA 40 mg q.i.d. (n ⫽ 253) 10.4 34.1 4.3 10.4 32.8 3.9 10 37 5.6 6 36 4.7 10 33 4.8 8 34 4.8 50.5 39.1 62.0 53.1 12.6 42.2 4.8 26.7 mo. 56.1 12.2 40.3 4.6a 22.5b mo. 46.3 Hormone receptor anastrozole versus MA 0.94 (P ⫽ 0.49; 97.5% CI, 0.76 –1.1). Hormone receptor anastrozole versus MA 0.78 (P ⫽ 0.0248; 97.5% CI, 0.6040 – 0.9996). In another report, exemestane exhibited potent aromatase inhibition in vivo and suppressed plasma levels of estrogens to the limits of detection of current assays (25). In conclusion, it appears that the most effective aromatase inhibitors can provide near maximal suppression of plasma estrogens, irrespective of their precise mode of inhibition of aromatase. It is clear that the newer-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, provide greater suppression of estrogens than the earlier aromatase inhibitors, aminoglutethimide, fadrozole, and formestane. The clinical data available for the newer aromatase inhibitors versus the previous standard therapies, megestrol acetate and tamoxifen (see below), indicate that step-changes in estrogen suppression are clinically important. However, the clinical relevance of the small differences in estrogen suppression between the newer aromatase inhibitors remains to be established. Ultimately, only direct head-to-head comparative clinical studies will provide the answers to these questions. Clinical Efficacy Second- and Third-line Therapy in Advanced Breast Cancer with Nonsteroidal Aromatase Inhibitors Anastrozole versus Megestrol Acetate. In 1995, anastrozole was the first of the newer-generation aromatase inhibitors to become clinically available for second-line therapy in postmenopausal women with advanced breast cancer failing on an antiestrogen, usually tamoxifen. This came after the results of two large, Phase III studies, which were performed in parallel, comparing oral anastrozole (1 mg or 10 mg, once daily) with oral megestrol acetate (40 mg four times daily) in postmenopausal women with advanced breast cancer who had progressed on tamoxifen (54, 55). The designs of each trial [one conducted predominantly in Europe (n ⫽ 378) and the other in North America (n ⫽ 386)] were identical and prospectively intended to allow the data to be combined to strengthen the overall statistical reliability of the trial results (56). Each trial was a multicenter, randomized, controlled, parallel group, doubleblind for each anastrozole arm and open-label for megestrol acetate. The primary objectives were to compare the three treatment groups in terms of TTP and OR (OR ⫽ CR ⫹ PR), and the secondary objectives were survival, time to TTF, and response duration. Rigorous criteria for assignment of objective response were applied on the basis of a strict interpretation of UICC guidelines (6, 57, 58). At a median follow-up of ⬃6 months, a combined analysis of the above two trials showed that approximately one-third of patients who were treated with either anastrozole (1 mg or 10 mg, once daily) or megestrol acetate (160 mg daily) derived clinical benefit from their treatment (58). There were no statistically significant differences among the three treatment arms in terms of efficacy (tumor response or TTP) in either trial. The data were too immature for an analysis of survival to be performed at that time. Intent-to-treat analyses were subsequently performed on the mature combined data from the two trials (62% of patients had died), when the median follow-up was 31.2 months (6). At the clinical dose of 1 mg daily, anastrozole demonstrated a statistically significant survival advantage over megestrol acetate, with a HR of 0.78 (P ⬍ 0.025). The median duration of survival was 26.7 months for the anastrozole 1 mg group compared with 22.5 months for the megestrol acetate group. The HR indicated that patients treated with anastrozole 1 mg were 22% less likely to die over a given time period than patients treated with megestrol acetate. Patients receiving anastrozole 10 mg daily also showed a survival benefit compared with the patients receiving megestrol acetate, with an HR of 0.83 and a median duration of survival of 25.5 months (P ⫽ 0.0951), but this difference was not statistically significant. The estimated 2-year survival rates from the combined analysis were 56.1%, 54.6%, and 46.3% for patients receiving anastrozole 1 mg, anastrozole 10 mg, or megestrol acetate, respectively. Clinical benefit was seen in ⬃40% of patients in all three groups (42.3% with anastrozole 1 mg). The data from the individual and combined analyses of these trials are summarized in Table 1. The authors concluded that the combined analysis clearly demonstrated that, after disease progression with tamoxifen, anastrozole 1 mg provides a statistically and clinically significant advantage over standard treatment with megestrol acetate. There was no additional benefit observed for anastrozole 10 mg over anastrozole 1 mg in terms of any of the primary end points. These results confirmed the choice of the 1 mg dose for use in clinical practice. In an additional subgroup analysis of the above combined trial data, it was shown that anastrozole was effective in patients Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. 2624 Aromatase Inhibition in Breast Cancer Treatment Table 2 An overview of efficacy results from Phase III trials of second-line treatment of newer aromatase inhibitors versus megestrol acetate (MA) in patients who have failed on tamoxifen European and US trials combined analysis6 Dose Aa 1 mg o.d. (n ⫽ 263) Median follow-up (mo) Median TTP (mo) 4.8 MA 40 mg q.i.d. (n ⫽ 253) European trial61 L 2.5 MA 40 mg o.d. mg q.i.d. (n ⫽ 174) (n ⫽ 189) 31 a 26.7 P ⬍ 0.025 L 2.5 mg o.d. MA 40 mg q.i.d. 33 4.6 5.6 22.5 25.3 NS Median survival (mo) US trial62 5.5 NS 21.5 NS No data published NS No data published International trial71 E 25 MA 40 mg o.d. mg o.d. (n ⫽ 366) (n ⫽ 403) 11 4.7 3.8 P ⫽ 0.037 NR 28.4 P ⫽ 0.039 A, anastrozole; L, letrozole; E, exemestane; NS, nonsignificant; NR, not reported. with advanced breast cancer with visceral and liver metastases (59). The median duration of clinical benefit in patients with visceral metastases was 16.4 months with anastrozole 1 mg (n ⫽ 263) compared with 14.7 months for megestrol acetate (n ⫽ 253); for liver metastases, the median duration of clinical benefit was 17.9 months with anastrozole 1 mg compared with 9.9 months for megestrol acetate. Furthermore, in a recent report, overall survival in patients with advanced breast cancer under assessment in one of the large-scale, comparative Phase III trials described above (58) was examined in relation to response type, i.e., the survival outcome based on whether patients demonstrated either CR/PR or SD ⱖ24 weeks (termed “long SD”; Ref. 60). For anastrozole (1 mg daily), there was no difference in estimates of 2-year survival between patients having either CR/PR or long SD. A similar result was obtained with patients treated with megestrol acetate (40 mg p.o. four times daily). These data confirmed the clinical value of long SD as an important end point in the measure of clinical efficacy in postmenopausal patients with advanced breast cancer, with predictive value for overall survival. Letrozole versus Megestrol Acetate. Two doses of oral letrozole (2.5 mg or 0.5 mg, once daily) were compared against each other and against megestrol acetate (160 mg once daily) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogen endocrine therapy (61). The trial design was multicenter, randomized, controlled, double-blind, in 551 patients with locally advanced, locoregionally recurrent, or advanced breast cancer. The primary efficacy end point was overall objective tumor response (CR ⫹ PR), assessed by UICC criteria (62). Secondary end points included TTP, TTF, and overall survival time. A higher overall OR rate was obtained for letrozole 2.5 mg compared with letrozole 0.5 mg (P ⫽ 0.004) or megestrol acetate (P ⫽ 0.04). The clinical benefit in each letrozole arm was ⬍35% (61). For TTP, letrozole 2.5 mg (5.6 months) was found to be superior to letrozole 0.5 mg (5.1 months; P ⫽ 0.02) but not to megestrol acetate (5.5 months; P ⫽ 0.07; Table 2). For overall survival, there was a significant dose effect for letrozole 2.5 mg (25.3 months; P ⫽ 0.03) over letrozole 0.5 mg (21.5 months), although letrozole 2.5 mg showed no significant survival advantage over megestrol acetate, even at an updated analysis at a follow-up of 51 months (63). The authors concluded that letrozole 2.5 mg was superior to the 0.5 mg dose and more effective than megestrol acetate in the treatment of ad- vanced breast cancer in postmenopausal women previously treated with an antiestrogen (61, 63). In contrast, however, in a second similar, randomized, controlled trial performed at the same time in North America, which has not yet been published in full, letrozole did not show this dose-dependent antitumor activity. Furthermore, there were no statistically significant differences in terms of OR, TTP, or survival with the 2.5-mg dose of letrozole compared with megestrol acetate; however, the 0.5 mg dose showed improved TTP over the progestin (64).3 Letrozole versus Aminoglutethimide. In an open-label, randomized trial, oral, once-daily letrozole (2.5 mg and 0.5 mg) was compared with aminoglutethimide (250 mg twice daily) in 555 postmenopausal women with advanced breast cancer previously treated with antiestrogens (65). Patients in the aminoglutethimide arm received daily oral glucocorticoid supplementation (hydrocortisone 30 mg or cortisone acetate 37.5 mg). The primary end point was overall objective tumor response (CR ⫹ PR). The secondary end points were TTP, TTF, and duration of survival. Overall, no significant differences in OR were seen in patients receiving letrozole 2.5 mg or 0.5 mg or aminoglutethimide. The absence of a significant dose-response effect for the two letrozole doses (0.5 mg versus 2.5 mg) is in contrast to that found in the trial comparing the same two doses of letrozole (P ⫽ 0.03) with megestrol acetate in a similar patient population (61, 63).3 Letrozole 2.5 mg was, however, statistically significantly superior to aminoglutethimide in terms of overall survival, TTP, and TTF in postmenopausal women with advanced breast cancer previously treated with antiestrogens. Vorozole: Open-Label, Phase III Trials. In an openlabel, multicenter, parallel-group Phase III trial, a total of 452 postmenopausal women with advanced breast cancer failing on tamoxifen were treated with either oral vorozole (2.5 mg once daily) or megestrol acetate (40 mg four times daily; Ref. 66). The primary end point was overall response rate. No significant differences were found between the two groups for overall response rate, clinical benefit [CR ⫹ PR ⫹ NC (no change) in ⱖ6 months], TTP, or survival. It was concluded that vorozole and megestrol acetate had similar efficacy in the treatment of 3 Internet address: http://fda.gov/ohrms/dockets/ac/backgrd/3671b_01.doc. Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2625 postmenopausal women with advanced breast cancer progressing on tamoxifen. In a second open-label, centrally randomized, multicenter Phase III trial, postmenopausal women with advanced breast cancer failing on tamoxifen therapy were treated with either oral vorozole (2.5 mg once daily; n ⫽ 211) or aminoglutethimide (250 mg twice daily; n ⫽ 213) until disease progression or death (67). The patients in the aminoglutethimide arm also received supplementary oral hydrocortisone (30 mg daily). There was a higher overall response rate for patients receiving vorozole compared with aminoglutethimide (24% versus 17%; P ⫽ 0.07); but in terms of duration of response, TTP, TTF, and survival time, no differences were found between the two treatment arms. It was therefore concluded that vorozole and aminoglutethimide were equivalent with respect to clinical efficacy. Although another open-label, comparative trial in postmenopausal patients with advanced breast cancer showed that vorozole (2.5 mg daily) appeared to be superior to aminoglutethimide (250 mg twice daily) plus hydrocortisone (30 mg once daily), in terms of response rate and clinical benefit (CR ⫹ PR ⫹ NC ⱖ 6 months; P ⫽ 0.07 and P ⫽ 0.017, respectively; Ref. 68), none of the studies involving vorozole has shown a significant advantage over megestrol acetate or aminoglutethimide in terms of either TTP or overall survival. Vorozole is no longer in clinical development. Fadrozole versus Megestrol Acetate. At present, fadrozole is only clinically available in Japan. Two prospective, randomized, double-blind Phase III trials of similar design were initiated to compare fadrozole with megestrol acetate in 683 postmenopausal women with advanced breast cancer, who had progressed on first-line or adjuvant hormonal therapy (69). The primary efficacy end point was OR. Other efficacy end points were TTP and survival. In the first trial, 380 patients were randomized to receive either fadrozole (1 mg twice daily) or megestrol acetate (40 mg four times daily), and in the second trial, 303 patients also received a similar regimen. Both treatment arms in each of the two trials received matching placebos. There were no differences in the response rates from either trial between fadrozole and megestrol acetate. The median survival time was longer in the fadrozole group than in the megestrol acetate group in the first trial (26.8 versus 22.8 months, respectively) and in the megestrol acetate group compared with the fadrozole group (25.4 versus 27.5 months, respectively) in the second trial (69). Neither trial showed any significant differences between the two treatments in terms of primary and secondary end points, confirming equivalence of fadrozole and megestrol acetate as second-line endocrine therapy in postmenopausal women with advanced breast cancer. Second- and Third-Line Therapy in Advanced Breast Cancer with Steroidal Aromatase Inhibitors Formestane versus Megestrol Acetate. In a prospective, randomized, crossover Phase III trial, formestane (250 mg i.m. every 14 days) was compared with megestrol acetate (160 mg p.o. daily) in 179 postmenopausal patients with advanced breast cancer who were failing on tamoxifen (24). The trial was planned to test differences in TTF. There were no significant differences between formestane and megestrol acetate in re- sponse rates, SD (ⱖ6 months), or TTF (3.9 versus 3.7 months, respectively), and formestane was considered to be as effective as megestrol acetate in this patient population. A second open trial of formestane (250 mg i.m. every 2 weeks) versus megestrol acetate (160 mg p.o. once daily) compared the efficacy and safety of the two drugs as second-line therapy in 547 receptorpositive or receptor-unknown postmenopausal patients with advanced breast cancer previously treated with tamoxifen (70). There were no significant differences between formestane and megestrol acetate in terms of median TTF and overall survival. Formestane was considered a suitable alternative to progestins in patients previously treated with tamoxifen. Exemestane versus Megestrol Acetate. In a randomized, double-blind Phase III trial, 769 postmenopausal women with advanced breast cancer refractory to tamoxifen were randomized to receive either exemestane (25 mg p.o. daily; n ⫽ 366) or megestrol acetate (40 mg p.o. four times daily; n ⫽ 403; Ref. 71). The overall median duration of follow-up was 48.9 weeks. At the time of data cutoff, median survival had not been reached, and 143 patients were still receiving study medication. The study was designed to demonstrate equivalence between treatment arms. The OR rate was similar in both groups, as was the rate of overall success (CR ⫹ PR ⫹ SD ⱖ 24 weeks; 37.4% for exemestane and 34.6% for megestrol acetate; not statistically significant). Both median TTP (P ⫽ 0.037) and median survival (P ⫽ 0.039), however, were significantly improved in those patients receiving exemestane (Table 2). It was concluded that, compared with megestrol acetate in postmenopausal women with advanced breast cancer refractory to tamoxifen, exemestane significantly delays tumor progression and significantly prolongs survival. Summary and General Conclusions. Anastrozole, letrozole, and exemestane have all demonstrated improved clinical efficacy over megestrol acetate in the second-line treatment of postmenopausal women who have failed on tamoxifen. Although anastrozole and exemestane have both demonstrated significantly improved survival over megestrol acetate, there has been no statistically significant survival benefit reported with letrozole (63). All three aromatase inhibitors, anastrozole (1 mg, once daily), letrozole (2.5 mg, once daily) and exemestane (25 mg, once daily) have demonstrated clinical benefit in secondline use in postmenopausal with advanced breast cancer (6, 61, 71), and these newer-generation aromatase inhibitors are now established as the second-line agents of choice in this patient population. First-line Therapy in Advanced Breast Cancer with Nonsteroidal Aromatase Inhibitors Anastrozole. In a major, large-scale, clinical trial program, anastrozole (1 mg once daily) was compared with tamoxifen (20 mg once daily) as first-line therapy in postmenopausal women with advanced breast cancer in two international, multicenter trials involving a total of 1021 patients (72, 73). The two trials were performed in the United States/Canada (“North American” trial) and in Europe/South America/Australia (“European” trial). They were randomized, double-blind, doubledummy trials designed to determine whether or not the two treatments had equivalent efficacy in this patient population. Patients had to be eligible for endocrine therapy and have either Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. 2626 Aromatase Inhibition in Breast Cancer Treatment Fig. 3 Kaplan-Meier curve for median TTP (anastrozole versus tamoxifen; North American trial). Fig. 4 Kaplan-Meier curve for median TTP (anastrozole versus tamoxifen; European trial; receptor-positive patients). ER-positive and/or PgR-positive tumors or tumors of unknown receptor status. The patients were either newly diagnosed with advanced disease or had progressed subsequent to diagnosis and treatment for early disease. They may have received prior adjuvant endocrine therapy or chemotherapy; however, a drug-free period of at least 1 year was required for those who had received adjuvant tamoxifen. The primary end points of the trials were TTP, OR, and tolerability. There were nine prespecified adverse events for which a statistical analysis was performed. The secondary end points were TTF and survival. The studies were designed prospectively to allow combined analysis of the data and were “powered” for equivalence. In total, 353 patients from 97 centers in the United States and Canada were entered into the North American trial (anastrozole, n ⫽ 171; tamoxifen, n ⫽ 182) and followed for a median of 18 months (73). The two patient groups were well balanced with respect to demographic data, and a positive tumor ER status was confirmed in 89% of patients. Median TTP was 11.1 months for anastrozole versus 5.6 months for tamoxifen (P ⫽ 0.005; two-sided; Fig. 3). On the basis of the derived HR of 1.44, at any given time point, patients receiving tamoxifen were 44% more likely to progress than those treated with anastrozole. OR was 21% for anastrozole and 17% for tamoxifen. Clinical benefit rates were 59% for anastrozole and 46% for tamoxifen (P ⫽ 0.0098; two-sided retrospective analysis). These data suggest that anastrozole is superior to tamoxifen as a first-line treatment of advanced breast cancer in postmenopausal women. In the second trial (European), 668 postmenopausal women with advanced breast cancer (anastrozole, n ⫽ 340; tamoxifen, n ⫽ 328) from 83 centers worldwide were recruited and followed for a median of 19 months (72). The two patient groups were again well balanced with respect to demographic data, but a positive tumor ER status was only reported in ⬃45% of patients. In this trial, median TTP was 8.2 and 8.3 months, and OR was 32.9 and 32.6% in the anastrozole and tamoxifen arms, respectively, confirming that anastrozole was at least as effective as tamoxifen in terms of the primary efficacy end points. Clinical benefit rates were 56.2% for anastrozole and 55.5% for tamoxifen. This difference in the TTP results between the two trials has mainly been attributed to the percentage of patients with confirmed positive tumor ER. An exploratory subgroup analysis for the 45% of ER-positive patients in the European trial showed a median TTP of 8.9 months on anastrozole compared with 7.8 months on tamoxifen (Fig. 4; Ref. 72). A prospectively planned combined analysis was performed on the efficacy and tolerability data from the total of 1021 patients recruited into the two trials (74). The data obtained in this large patient population indicate that anastrozole is at least as effective as tamoxifen for the treatment of postmenopausal women with advanced breast cancer, with an observed advantage in terms of TTP: median TTP was 8.5 months for anastrozole and 7 months for tamoxifen (HR ⫽1.12; lower 95% CI, 1.00; Table 3). A total of 57% of patients on anastrozole showed clinical benefit compared with 52% on tamoxifen. A subgroup analysis was performed on the combined data from the European and North American trials. These analyses confirmed that receptor status was a key factor affecting the relative efficacy of anastrozole in relation to tamoxifen. Anastrozole showed a statistically significant advantage over tamoxifen in median TTP (P ⫽ 0.022; two-sided, retrospective analysis) in a combined analysis of 611 patients who were known to be ER-positive/PgR-positive (75). The significance of whether or not prior adjuvant treatment impacted treatment outcome was investigated in the combined first-line trial population. Overall, 14.2% of patients had received prior hormonal therapy, 19.5% in the North American trial and 11.4% in the European trial.4 In 97% of cases, the prior adjuvant hormonal therapy was tamoxifen. Although no formal statistical analyses within subgroups were carried out, the data observed for TTP and OR rates in those patients not receiving prior adjuvant hormonal therapy were similar to those observed in patients who did receive therapy, which in turn is similar to data for the overall patient population.4 These data on the efficacy of anastrozole in the first-line setting versus tamoxifen are supported by the results of a recently reported, independent, prospective, randomized, first-line study in which 238 postmenopausal women with hormonesensitive, ER-positive, metastatic breast cancer, who had not received previous therapy for advanced disease, were treated with either anastrozole (1 mg once daily; n ⫽ 121) or tamoxifen (40 mg daily; n ⫽ 117) (76). At the time of data cutoff, 61% of 4 AstraZeneca; data on file. Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2627 Table 3 Overview of efficacy results from Phase III first-line trials of newer aromatase inhibitors versus tamoxifen in postmenopausal women with advanced breast cancer Anastrozole: combined US and European trials75 Anastrozole: Spanish trial76 Letrozole: US trial only77 Parameter Anastrozole 1 mg daily Tamoxifen 20 mg daily Anastrozole 1 mg daily Tamoxifen 20 mg daily Letrozole 1 mg daily Tamoxifen 20 mg daily Median TTP (mo) HR⫹veb patients only 8.5 10.7 7.0a 6.4 P ⫽ 0.022 (two-sided) 10.6 9.4 6.0 P ⫽ 0.0001 (two-sided) Survival rate NMb 5.3 HR ⫽ 0.77 (95% CI 0.56–0.91; P ⬍ 0.05) 92% died HR ⫽ 0.63; (95% CI 0.51–0.89; P ⬍ 0.05) a b 61% died NM Not significant. HR⫹ve, hormone receptor-positive; NM, data not yet mature. patients had died in the anastrozole-treated group, compared with 92% in the tamoxifen-treated group (HR ⫽ 0.63; 95% CI, 0.51– 0.89; P ⬍ 0.05; Table 3). Median TTP was 10.6 months for anastrozole and 5.3 months for tamoxifen, with a higher risk of progression in the tamoxifen group, as indicated by the HR of 0.77 (95% CI, 0.56 – 0.91; P ⬍ 0.05) (79). It was the conclusion of all of these studies that anastrozole should now be considered as an alternative first-line treatment to tamoxifen in postmenopausal women with advanced breast cancer. Letrozole. Preliminary data have recently been reported from a large, multicenter, double-blind, first-line Phase III clinical trial in postmenopausal women (n ⫽ 907) with locally advanced or metastatic breast cancer, which compared letrozole (2.5 mg once daily) with tamoxifen (20 mg once daily; Ref. 77). The primary end point was TTP and secondary end points included OR, TTF, time to response, and survival. A total of 65% of patients had ER-positive/PgR-positive status. Statistically significant superiority for letrozole was shown for the primary end point, TTP (median TTP, 9.4 months for letrozole versus 6.0 months for tamoxifen; P ⫽ 0.0001; Cox regression; Table 3). In contrast to the anastrozole trials, prior adjuvant tamoxifen in this trial was seen to impact upon subsequent response to treatment. For instance, after adjuvant tamoxifen, patients receiving tamoxifen for metastatic disease were seen to have a low response rate compared with letrozole (29% versus 8% for letrozole and tamoxifen, respectively). Additional data and a full publication from this trial are awaited. Fadrozole. In a Phase III randomized trial, fadrozole (1 mg twice daily) was compared directly with tamoxifen (20 mg once daily) as first-line therapy in the treatment of 221 postmenopausal women with advanced breast cancer (78). The study was not double-blind, and patients with disease progression or an unacceptable level of toxicity were given the opportunity to cross over to the alternative drug where feasible. The two groups were well balanced with respect to prognostic factors except for metastatic disease; patients in the fadrozole arm had significantly more visceral metastases and disease than those in the tamoxifen arm. There was no significant difference between treatments in terms of OR rate. TTF was longer with tamoxifen (8.5 months) compared with fadrozole (6.1 months; P ⫽ 0.05; P ⫽ 0.09, after Fig. 5 Kaplan-Meier curve for median TTF (fadrozole versus tamoxifen). adjustment for prognostic factors; Fig. 5), although duration of response and survival were comparable in the two groups. First-line Therapy in Advanced Breast Cancer with Steroidal Aromatase Inhibitors Formestane. In a comparative trial of first-line therapy for postmenopausal women with advanced breast cancer, the steroidal aromatase inhibitor, formestane (250 mg i.m. every 2 weeks), gave comparable results to those of tamoxifen (30 mg p.o. daily) for both efficacy and tolerability (43). In total, 409 patients were randomized into two groups, well matched for pretreatment characteristics, although there was a higher proportion of patients with soft tissue metastases in the formestanetreated group compared with the tamoxifen-treated group. Patients were assessed for antitumor efficacy using UICC criteria. A total of 61 patients were not evaluable, either because they were not eligible for the trial (mainly attributable to a lack of confirmation of postmenopausal status) or because they were nonevaluable for tumor response. There were no statistically significant differences found between the two groups (n ⫽ 348) for OR, median duration of response, and survival. However, results significantly favored tamoxifen compared with formestane in terms of TTP (9.7 months versus 7.0 months, respectively; adjusted P ⫽ 0.003) and TTF (9.7 months versus 6.5 months; adjusted P ⫽ 0.001) compared with formestane. Exemestane. A Phase II study was recently conducted in which exemestane (25 mg daily) was compared with tamoxifen Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. 2628 Aromatase Inhibition in Breast Cancer Treatment Table 4 Tolerability data: indirect comparison of newer aromatase inhibitors versus megestrol acetate in second-line trials Adverse event (%) Anastrozolea 1 mg o.d.b Letrozolea 2.5 mg o.d.c Exemestane71 25 mg o.d.d Megestrol acetate 160 mg q.i.d. Headache Hot flushes Nausea Vomiting Diarrhea Weight gain Rash Dyspnea Asthenia Fatigue 14 13 18 10 9 3 6 11 18 NA 13 6 11 8 6 6 6 9 NAf 11 NA 13 9 3 NA 8e 2 1 NA 8 9–13 4–11 5–23 5–7 3–11 9–17 3–12 3–28 7–20 10–22 a Adapted from Ref. 83. Commonly reported adverse events, irrespective of causality. c Adverse experiences in ⬎5% of patients, irrespective of causality. d Adverse events considered to be drug-related. e Incidence of weight gain from baseline. f NA Data not available in published literature. b (20 mg daily) as first-line treatment of metastatic breast cancer in postmenopausal women (n ⫽ 93; Ref. 79). Median TTP for exemestane (n ⫽ 31) was 8.9 months compared with 5.2 months for tamoxifen (n ⫽ 32), and OR (CR ⫹ PR) was 42% versus 16%, respectively. No statistical data from this Phase II study are available at the present time. It was concluded that exemestane had promising activity in the first-line treatment of metastatic disease and warranted a Phase III trial. Conclusions. The results of the first-line Phase III comparative trials between anastrozole and tamoxifen now support the use of anastrozole in the first-line treatment of advanced disease in postmenopausal women. Notwithstanding earlier investigations into the first-line use of the aromatase inhibitors fadrozole and formestane, compared with tamoxifen in advanced breast cancer in postmenopausal women, this is the first full report from a large-scale, randomized study of a newergeneration aromatase inhibitor having superior efficacy to that of tamoxifen. Preliminary data have recently been reported showing a statistically significant advantage for letrozole versus tamoxifen in terms of TTP in the first-line treatment of advanced disease, and a full report of these data are awaited. Tolerability of Steroidal and Nonsteroidal Aromatase Inhibitors Adverse Events. In clinical use, both steroidal and nonsteroidal aromatase inhibitors are generally well tolerated. The main adverse events observed are hot flushes and gastrointestinal events, i.e., nausea and vomiting, which are either anticipated via the pharmacological actions of aromatase inhibitors or are the most commonly seen type of events with this class of drug (18, 21, 43, 71, 72, 80 – 82). There are, however, certain specific side effects observed with exemestane, but not anastrozole and letrozole, that relate to the androgenic nature of the drug. When compared with megestrol acetate in second-line studies in advanced breast cancer, the nonsteroidal drugs, anastrozole and letrozole, were associated with a significantly lower incidence of weight gain (55, 61). When exemestane was compared with megestrol acetate, there was also a significantly lower incidence of weight gain with exemestane (P ⫽ 0.001), as would be anticipated when comparing aromatase inhibitors with progestins in this patient population (71). However, the observed value for grade 3– 4 weight gain (excessive weight gain ⬎10% of baseline weight) of 7.6% in patients receiving exemestane is higher than that reported for the nonsteroidal aromatase inhibitors, anastrozole and letrozole, in similar trials in a comparable patient population (Table 4; Refs. 55 and 61); this higher value for exemestane probably reflects the androgenic nature of the drug. Additionally, weight gain changes of ⱖ10% after exemestane were noted in 4% of overweight patients (71). At higher than normal therapeutic doses of exemestane (200 mg daily), androgenic events have been reported, such as alopecia (10%), hypertrichosis (55), hoarseness (5%), and acne (4%; Ref. 84). Exemestane has been reported to lead to statistically significant dose-dependent falls in plasma sex hormone binding globulin levels at the 25-mg dose level (52). At 200 mg daily, exemestane gave rise to a case of mild hirsutism after 52 weeks’ treatment. In a Phase II trial, symptoms which may have been androgenic in nature were reported, again using the clinical dose of exemestane of 25 mg daily (two cases of grade 1 alopecia, one patient each with hypertrichosis and acne among 91 treated patients; Ref. 53). In a Phase III trial comparing exemestane and megestrol acetate, significantly more women receiving exemestane experienced hot flushes (12.0% versus 5.0%), nausea (9.2% versus 5.0%), and vomiting (2.8% versus 0.8%) than did women receiving megestrol acetate, respectively. Significantly more women receiving megestrol acetate reported dyspnoea than did women receiving exemestane (3.0% versus 0.3%, respectively; Ref. 71). In a first-line study comparing fadrozole with tamoxifen, a 4% incidence in thromboembolic events was reported in the tamoxifen group, whereas no events were observed in fadrozoletreated patients (78). In the first-line studies comparing anastrozole with tamoxifen (72–75), anastrozole-treated patients had a significantly lower incidence of thromboembolic events (combined analysis).4 With respect to other adverse events in these same trials, more patients treated with anastrozole had hot Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2629 flushes and vaginal dryness, whereas more patients treated with tamoxifen had vaginal bleeding and vaginal discharge, although the differences were not significant. Although gastrointestinal disturbances are widely recognized as a class effect of aromatase inhibitors, it should be noted that that the incidence of gastrointestinal disturbances was similar in the cases of anastrozole and tamoxifen in each trial [24% anastrozole versus 28% tamoxifen, respectively (72) and 54% anastrozole versus 57% tamoxifen, respectively (73)]. Finally, despite its lack of estrogenic effect, anastrozole showed no increase in myocardial infarction or fractures compared with tamoxifen. Overall, very few patients withdrew from first- or secondline comparative Phase III trials because of drug-related adverse events with aromatase inhibitors (19, 54, 55, 61, 66, 72, 73). In the large-scale, randomized trials of anastrozole versus tamoxifen for first-line treatment, the incidence of withdrawals was similar in both treatment groups, showing that anastrozole is at least as well tolerated as tamoxifen (72, 73). No tolerability data are available, as yet, from the first-line study comparing letrozole with tamoxifen (77). The newer-generation aromatase inhibitors have the additional advantage of simple, oral, once-daily dosing. This avoids such problems as local reactions (7–13%) at the site of injection, which have been reported after the twice-weekly i.m. administration of the steroidal aromatase inhibitor, formestane, thus limiting the potential, long-term usefulness of this drug in the adjuvant setting (11, 12, 43, 85). Neoadjuvant Therapy with Aromatase Inhibitors Anastrozole. A small, randomized, double-blind, singlecenter study was performed in which anastrozole (1 mg and 10 mg daily, for 3 months) was used as neoadjuvant therapy in 23 postmenopausal women with newly diagnosed, ER-rich, locally advanced, or large (⬎3 cm), operable breast tumors (86). Anastrozole at the normal clinical dose of 1 mg daily was shown by ultrasound measurements to be effective in leading to a decrease in tumor volume in the great majority of patients (80.5%). This had a dramatic influence on subsequent breast surgery, in that, of 17 patients who would have required mastectomy at the initiation of treatment, 15 were found to be suitable for breast conservation after 3 months’ treatment with anastrozole. These results suggest that anastrozole is highly effective as neoadjuvant therapy in postmenopausal women with ER-rich breast tumors. In the same group of patients, anastrozole was shown to suppress effectively aromatase activity within the breast, thereby reducing endogenous estrogens (87). This observation is compatible with the known antitumor effects of anastrozole. In another small study in 12 postmenopausal women with locally advanced (T3–T4) breast cancer, anastrozole 1 mg daily for 15 weeks was evaluated for its effects on plasma and tumor tissue estrogen levels in the same patient group (88). Treatment with anastrozole suppressed tumor tissue concentrations of estradiol, estrone, and estrone sulfate by 88.9%, 82.3%, and 73.4%, respectively, and plasma concentrations by 86.1%, 83.9%, and 95.8%, respectively. It was concluded that anastrozole is a potent suppressor of plasma and intratumoral estrogen levels in patients with locally advanced breast cancer. Letrozole. In a similar study, letrozole 2.5 mg daily for 3 months as primary medical therapy was investigated for its effects on in situ estrogen synthesis in 11 postmenopausal women with large, primary, ER-positive breast tumors (89). Of 10 tumors which showed evidence of in situ estrogen synthesis, 9 displayed a significant decrease in activity after letrozole treatment (P ⫽ 0.022 by sign test). It was concluded that letrozole brought about a decrease in endogenous levels of estrogen within the breast tumors of postmenopausal women. Letrozole (2.5 mg daily; n ⫽ 12; 10 mg daily, n ⫽ 12) was administered to 24 patients with ER-positive breast tumors as primary systemic therapy (90). The patients were monitored by monthly ultrasound and change in tumor volume over a 3-month period. The resulting median reduction in tumor volume was 81%. Fifteen patients who would have been considered for mastectomy before letrozole therapy were found to be suitable for breast conservation after 3 months’ treatment with the drug. In a double-blind, randomized, multicenter study, letrozole (2.5 mg daily) was compared with tamoxifen (20 mg daily) as neoadjuvant treatment of 337 postmenopausal women with ERpositive primary breast cancer, over a 4-month period (91). All patients at baseline were not considered eligible for breastconserving surgery. The primary end point was tumor response. Another important end point was the resultant impact of treatment on the down-staging of the extent of surgery. OR rates were 55% for letrozole (n ⫽ 154) versus 36% for tamoxifen (n ⫽ 170), a difference which was statistically significantly different (P ⬍ 0.001; Mantel-Haenszel low rank test). After 4 months’ therapy, 45% of letrozole-treated patients underwent a lumpectomy/quadrantectomy versus 35% of tamoxifen-treated patients (P ⫽ 0.022; Mantel-Haenszel). It was concluded that letrozole was significantly superior to tamoxifen in terms of tumor reduction, which resulted in a superior rate of breastconserving surgery in the letrozole-treated group. Conclusions. From the results of the above studies, both anastrozole and letrozole are shown to be effective as neoadjuvant therapy in postmenopausal women with large, operable breast tumors. Treatment for up to 3 months with either aromatase inhibitor led to a marked reduction in mastectomy rates. Results to date for letrozole versus tamoxifen, and from an indirect comparison of anastrozole with tamoxifen as neoadjuvant therapy in a similar patient population, indicate that these newer-generation aromatase inhibitors appear to offer an advantage over neoadjuvant therapy with antiestrogens, and additional comparative studies between these two classes of endocrine agents are under way. Adjuvant Therapy with Aromatase Inhibitors Tamoxifen is the most widely used endocrine agent for the adjuvant therapy of early breast cancer in postmenopausal women (79). Nevertheless, tamoxifen does have limitations in use, most notably its recognized pharmacological properties and side effects. For instance, tamoxifen has been associated with an increased risk of both thromboembolic events and endometrial changes, including endometrial cancer (9, 92). It is feasible, therefore, that other endocrine drugs can provide at least equivalent, if not superior, efficacy, together with improved tolerability, in patients with early disease. In this context, the newergeneration aromatase inhibitors are now under investigation in the adjuvant setting (Table 5). Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. 2630 Aromatase Inhibition in Breast Cancer Treatment Table 5 Key adjuvant studies with aromatase inhibitors (see Refs. 81, 82, 91, and 92) Adjuvant study ATAC ARNO ABCSG FEMTABIG MA.17 ICCG NSABP (B-33) Design Tamoxifen alone (20 mg daily, 5 yr) versus Tamoxifen (20 mg daily) ⫹ anastrozole (1 mg daily, 5 yr) versus Anastrozole alone (1 mg daily 5 yr) Tamoxifen (20 mg daily, 2 yr) followed by tamoxifen (20 mg daily, 3 yr) versus Tamoxifen (20 mg daily, 2 yr) followed by anastrozole (1 mg daily, 3 yr) Comparison of addition of aminoglutethimide to tamoxifen for 5 yr, followed by rerandomization to compare anastrozole with placebo for an additional 3 yr Tamoxifen (20 mg daily) versus anastrozole (1 mg daily) after 2-yr exposure to tamoxifen (20 mg daily) Tamoxifen (20 mg daily, 5 yr) versus Letrozole (2.5 mg daily, 5 yr) versus Letrozole (2.5 mg daily, 2 yr) followed by tamoxifen (20 mg daily, 3 yr) versus Tamoxifen (20 mg daily, 2 yr) followed by letrozole (2.5 mg daily, 3 yr) Tamoxifen (5 yr) followed by letrozole (5 yr) versus Tamoxifen (5 yr) followed by placebo (5 yr) Tamoxifen (20 mg daily, 2–3 yr) followed by either tamoxifen (20 mg daily) or exemestane (25 mg daily) for the remainder of the 5-yr period Tamoxifen (5 yr) followed by either exemestane (25 mg daily) for 2 yr or placebo for 2 yr Anastrozole. Anastrozole is currently being compared directly with tamoxifen as initial adjuvant therapy in postmenopausal women with early breast cancer (82, 93–95). The ATAC trial is a randomized, double-blind trial designed to compare the efficacy and tolerability of 5 years of treatment with tamoxifen with that of anastrozole versus the combination of anastrozole and tamoxifen (92, 93). The primary end points are time to recurrence and safety. Other criteria for evaluation include time to distant metastases, survival, and occurrence of contralateral breast cancer. Separate subprotocols include assessments of pharmacokinetics, endometrial status, bone mineral density, and quality of life. The ATAC trial has now completed recruitment of over 9300 patients and is expected to report in the year 2001. A second trial, the Arimidex-Nolvadex (ARNO) trial, being conducted by the German Breast Cancer Group, involves the randomization of patients who have received adjuvant tamoxifen for 2 years to receive either anastrozole for 3 years or tamoxifen for an additional 3 years (82, 92–94). The primary end points in this trial are overall survival, relapse-free survival, tolerability, and quality of life. Two other adjuvant studies of endocrine therapy with aromatase inhibitors in early breast cancer are in progress with the ABCSG (95). The first study compares the addition of the first-generation aromatase inhibitor, aminoglutethimide, to tamoxifen treatment in postmenopausal patients with hormoneresponsive, stage I and stage II breast cancer. After 5 years’ endocrine treatment in either arm, patients who are recurrencefree are being rerandomized to compare anastrozole with placebo for another 3 years. In the second ABCSG study, adjuvant tamoxifen for 3 years is being compared with adjuvant anastrozole for 3 years after 2 years’ exposure to tamoxifen in postmenopausal patients presenting with hormone-responsive, G1 and G2, stage I and stage II breast cancer. Letrozole. The Femera-Tamoxifen Breast International Group (FEMTABIG) trials of letrozole and tamoxifen are being conducted by the Breast International Group to compare letrozole with tamoxifen over 5 years in postmenopausal women with ER-positive/PgR-positive early breast cancer and to compare a sequence of adjuvant endocrine therapies versus a con- tinuous course of a single endocrine agent. The trial consists of an option of randomization into two single arms of either tamoxifen (20 mg daily) or letrozole (2.5 mg daily) for 5 years or randomization into a four-arm trial comprising either arm of the first option above (two-arm trial); and a third arm of 3 years of tamoxifen (20 mg daily) and then letrozole (2.5 mg daily) for 2 years; and a fourth arm of letrozole (2.5 mg daily) for 3 years and then tamoxifen (20 mg daily) for 2 years (81, 82, 92). Another adjuvant trial, the MA.17 study, evaluates patients from the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) who are disease-free after initially being treated with 5 years of tamoxifen and then randomized to receive either 5 years of placebo or 5 years of letrozole. This trial also incorporates assessments of incidence of bone fractures and bone mineral density measurements together with lipid profiles (81). Exemestane. The steroidal aromatase inhibitor, exemestane is also being studied in the adjuvant setting (81, 82, 92). In the International Collaboration Cancer Group (ICCG) trial, patients with early breast cancer are randomized to receive tamoxifen (20 mg daily for 2–3 years) and then either tamoxifen (20 mg daily) or exemestane (25 mg daily) for the remainder of the 5-year period (92). In the National Surgical Adjuvant Breast and Bowel Project (NSABP; B-33) trial, patients with early breast cancer are being randomized to receive either exemestane or placebo for 2 years after a standard 5 years of tamoxifen therapy (82). Conclusions. The above adjuvant trials of aromatase inhibitors versus tamoxifen in the treatment of early breast cancer offer the opportunity for the measurement of parameters such as disease recurrence, contralateral breast cancer occurrence, disease-free survival, and overall survival. It is hoped that the current trials with anastrozole, letrozole, and exemestane as adjuvant endocrine treatment in early breast cancer will be beneficial in terms of efficacy, tolerability and quality-of-life parameters in postmenopausal women. The data from the ATAC trial will be available in the near future, and the recent data from the first-line comparative trials between anastrozole and tamoxifen and letrozole and tamoxifen suggest that there is also Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2631 Table 6 Properties of aromatase inhibitors Aromatase inhibitor Class Anastrozole Fadrozole Letrozole Nonsteroidal Nonsteroidal Nonsteroidal II: Inhibitor II: Inhibitor II: Inhibitor 1 mg daily p.o. 1 mg twice daily p.o. 2.5 mg daily p.o. Vorozole Nonsteroidal II: Inhibitor 2.5 mg daily p.o. Exemestane Formestane Steroidal Steroidal I: Inactivator I: Inactivator 25 mg daily p.o. 250 mg twice weekly i.m. Type Normal clinical dose and route of administration Phase III clinical data available for second-line use versus: Megestrol acetate6,54,55,58 Megestrol acetate69 Megestrol acetate61–63 Aminoglutethimide65 Megestrol acetate66 Aminoglutethimide67,68 Megestrol acetate71 Megestrol acetate24,70 Table 7 First-line clinical trials of aromatase inhibitors Phase III clinical data available for first-line use in advanced breast cancer. Aromatase inhibitor Major findings Anastrozole vs. tamoxifen72–75 Anastrozole at least as effective as tamoxifen. Significant difference in favor of anastrozole for patients with ER-positive and/or PgR-positive tumors (P ⫽ 0.022; two-sided). Numerical (nonsignificant) advantage for tamoxifen over fadrozole in terms of TTF. No significant difference in terms of OR rate. Duration of response and survival comparable. No statistically significant differences for OR, median duration of response, and survival. Results significantly favored tamoxifen compared with formestane in terms of TTP and TTF. Promising antitumor activity vs. tamoxifen in a Phase II study (n ⫽ 97). A Phase III trial is planned. Preliminary data available showing significant superiority for letrozole over tamoxifen in terms of TTP. No data available. Fadrozole vs. tamoxifen78 Formestane vs. tamoxifen43 Exemestane vs. tamoxifen79 Letrozole vs. tamoxifen77 Vorozole potential for aromatase inhibitors to provide an advantage over tamoxifen in the adjuvant setting. Overall Conclusions The data for the second-line use of endocrine therapy with steroidal and nonsteroidal aromatase inhibitors has fully established this class of drugs as the new treatment of choice in postmenopausal women with advanced breast cancer failing on prior treatment with an antiestrogen such as tamoxifen (20, 58, 61, 71). In terms of efficacy, anastrozole, letrozole, and exemestane each have shown advantages over the standard second-line therapy, megestrol acetate. Anastrozole was the first nonsteroidal, newer-generation aromatase inhibitor to demonstrate a mature efficacy and survival advantage over another second-line endocrine drug (58), although exemestane has now also been reported to improve survival compared with megestrol acetate (71). All of the newer-generation aromatase inhibitors are well tolerated, with hot flushes and gastrointestinal disturbance being the major adverse events reported in second-line comparative studies. The nonsteroidal aromatase inhibitors, anastrozole and letrozole, both display a clear benefit in terms of weight gain over megestrol acetate. The properties of aromatase inhibitors reviewed in this article are shown in Table 6. Many reviewers have attempted to draw indirect comparisons between drugs within this class of aromatase inhibitors in an effort to identify the optimal aromatase inhibitor for the second-line therapy of advanced breast cancer. This is fraught with difficulties, because randomized, controlled trials involving these agents have study designs with different response criteria and different methods of assessment in different patient populations (20, 80). As a result, such indirect comparisons between trials cannot possibly lead to a clear outcome in favor of any single drug. Some investigators even have attempted to reach conclusions based on the degree of estrogen suppression exhibited by aromatase inhibitors; but it should be noted that the net clinical relevance of plasma estrogen reduction still needs to be carefully evaluated (81). One major area of considerable interest for these newergeneration aromatase inhibitors lies in their potential for lack of cross-resistance with other drugs of the same class, thereby allowing the possibility for an additional response to endocrine therapy, even after progression on second-line treatment. This is illustrated by the response of patients to anastrozole after progression on second-line therapy with formestane (96); 9 of 12 patients who had initially achieved either a PR or SD on formestane before progressing showed additional SD on anastrozole. Seven of these nine responding patients had ER-positive tumors. Similarly, exemestane produced CR in 3 patients and PR in 13 patients when given to postmenopausal women with metastatic breast cancer after progression on second-line therapy with the nonsteroidal aromatase inhibitors, aminoglutethimide, anastrozole, letrozole, or vorozole (97). This lack of cross-resistance might be predicted when steroidal aromatase inhibitors are used sequentially after nonsteroidal aromatase inhibitors and vice versa because of their different mechanisms of action on the aromatase enzyme. The neoadjuvant use of newer-generation aromatase inhibitors in women with ER-rich, locally advanced, or large operable breast tumors gives rise to optimism because of their ability Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. 2632 Aromatase Inhibition in Breast Cancer Treatment to reduce mastectomy rates while providing an early indication of likely tumor response to endocrine therapy. In the first-line therapy of advanced breast cancer, anastrozole and letrozole have now challenged the position of the long-established, standard therapy, tamoxifen, showing significant benefits in terms of TTP (74, 77). Both aromatase inhibitors are very well tolerated, but anastrozole has shown fewer thromboembolic complications and instances of vaginal bleeding than tamoxifen and is not associated with an increased risk of endometrial cancer. Tolerability data for letrozole in this setting are not yet available. Undoubtedly, as more results from first-line trials become available (Table 7), aromatase inhibitors will become more widely used as first-line agents, as an alternative to tamoxifen, in the treatment of postmenopausal women with advanced disease. There are differences in both the chemistry and the pharmacological properties of the newer-generation aromatase inhibitors. These differences seem to have an impact upon selectivity of the drugs for aromatase (e.g., effect on adrenocorticorticotropic hormone-stimulated cortisol levels) and may possibly have an effect on the clinical efficacy of aromatase inhibitors in the adjuvant setting on a long-term basis. Data on the adjuvant use of anastrozole, letrozole, and exemestane will become available in the near future; data on anastrozole is expected to be the first to report. Although each of these aromatase inhibitors are generally well tolerated in the metastatic setting, it will be their tolerability profiles after long-term use in the adjuvant setting that will ultimately determine whether or not tamoxifen is replaced as the “gold standard” adjuvant treatment. It will be important to determine whether there are any long-term effects on the endometrium or on thromboembolic events and, additionally, whether any differences in “selectivity” between the drugs have any clinical consequences. Currently, there are no data available on possible interactions between aromatase inhibitors and standard chemotherapeutic agents. The ongoing clinical trial program will provide the answers to many of these points, the data being awaited with great interest. References 1. Beatson, G. T. On the treatment of inoperable cases of carcinoma of the mamma; suggestions for a new method of treatment with illustrative cases. Lancet, 2: 104 –107, 1896. 2. Coletta, A. A., Benson, J. R., and Baum, M. Alternative mechanisms of action of anti-oestrogens. Breast Cancer Res. Treat, 31: 5–9, 1994. 3. Butta, A., MacLennan, K., Flanders, K. C., Sacks, N. P. M., Smith, I., McKinna, A., Dowsett, M., Wakefield, L. M., Sporn, M. B., Baum, M., and Colletta, A. A. Induction of transforming growth factor  1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res., 52: 4261– 4264, 1992. 4. Cullen, K. J., Lippmann, M. E., Chow, D., Hill, S., Rosen, N., and Zwiebel, J. A. Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression. Mol. Endocrinol., 6: 91–100, 1992. 5. Leonard, R. C. F., Rodger, A., and Dixon, J. M. Metastatic breast cancer. Br. Med. J., 309: 1501–1504, 1994. 6. Buzdar, A. U., Jonat, W., Howell, A., Jones, S. E., Blomqvist, C. P., Vogel, C. L., Eiermann, W., Wolter, J. M., Steinberg, M., Webster, A., and Lee, D., 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 (Phila.), 83: 1142–1152, 1998. 7. Forbes, J. F. The control of breast cancer: the role of tamoxifen. Semin. Oncol., 24 (Suppl. 1): S1–5–S1–19, 1997. 8. Powles, T. J. Efficacy of tamoxifen as treatment of breast cancer. Semin. Oncol., 24 (Suppl. 1): S1– 48 –S1–54, 1997. 9. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet, 351: 1451–1467, 1998. 10. Santen, R. J., Santner, S., Davis, B., Veldhuis, J., Samojlik, E., and Ruby, E. Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J. Clin. Endocrinol. Metab., 47: 1257–1265, 1978. 11. Coombes, R. C. Aromatase inhibitors and their use in the adjuvant setting. Recent Results Cancer Res., 152: 277–284, 1998. 12. Wiseman, L. R., and Goa, K. L. Formestane. A review of its pharmacological properties and clinical efficacy in the treatment of postmenopausal breast cancer. Drugs Aging, 9: 292–306, 1996. 13. Roseman, B. J., Buzdar, A. U., and Singletary, S. E. Use of aromatase inhibitors in postmenopausal women with advanced breast cancer. J. Surg. Oncol., 66: 215–220, 1997. 14. Hortobagyi, G. N., and Buzdar, A. U. Anastrozole (Arimidex), a new aromatase inhibitor for advanced breast cancer: mechanism of action and role in management. Cancer Investig., 16: 385–390, 1998. 15. Wiseman, L. R., and Adkins, J. C. Anastrozole. A review of its use in the management of postmenopausal women with advanced breast cancer. Drugs Aging, 13: 321–332, 1998. 16. Lamb, H. M., and Adkins, J. C. Letrozole. A review of its use in postmenopausal women with advanced breast cancer. Drugs, 56: 1125– 1140, 1998. 17. Goss, P. E. Pre-clinical and clinical review of vorozole, a new third generation aromatase inhibitor. Breast Cancer Res. Treat., 49 (Suppl. 1): S59 –S65, 1998. 18. Locker, G. Y. Hormonal therapy of breast cancer. Cancer Treat. Rev., 3: 221–240, 1998. 19. Reddy, P. A review of the newer aromatase inhibitors in the management of metastatic breast cancer. J. Clin. Pharm. Ther., 23: 81–90, 1998. 20. Bajetta, E., Zilembo, N., and Bichisao, E. Aromatase inhibitors in the treatment of postmenopausal breast cancer. Drugs Aging, 15: 271– 283, 1999. 21. Lønning, P. E. Pharmacological profiles of exemestane and formestane, steroidal aromatase inhibitors used for treatment of postmenopausal breast cancer. Breast Cancer Res. Treat., 49 (Suppl. 1): S45–S52, 1998. 22. Costa, L. A. M., Kopreski, M. S., Demers, L. M., Chinchilli, V. M., Santen, R. J., Harvey, H. A., and Lipton, A. Effect of the potent aromatase inhibitor fadrozole hydrochloride (CGS 16949A) in postmenopausal women with breast carcinoma. Cancer (Phila.), 85: 100 – 103, 1999. 23. Howell, A., Downey, S., and Anderson, E. New endocrine therapies for breast cancer. Eur. J. Cancer, 32A: 576 –588, 1996. 24. Thürlimann, B., Castiglione, M., Hsu-Schmitz, S. F., Hsu-Schmitz, F., Cavalli, F., Bonnefoi, H., Fey, M. F., Morant, R., Löhnert, T., and Goldhirsch, A. Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a Phase III prospective randomized cross over trial of second-line hormonal treatment (SAKK 20/90). Eur. J. Cancer, 33: 1017–1024, 1997. 25. Geisler, J., King, N., Anker, G., Ornati, G., Di Salle, E., Lønning, P. E., and Dowsett, M. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin. Cancer Res., 4: 2089 –2093, 1998. 26. di Salle, E., Giudici, D., Briatico, G., and Ornati, G. Novel irreversible aromatase inhibitors. Ann. NY Acad. Sci., 595: 357–367, 1990. 27. Santen, R. J., Demers, L. M., Lynch, J., Harvey, H., Lipton, A., Mulagha, M., Hanagan, J., Garber, J. E., Henderson, I. C., Navari, Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2633 R. M., and Miller, A. A. Specificity of low-dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor. J. Clin. Endocrinol. Metab., 73: 99 –106, 1991. 28. Dowsett, M., Smithers, D., Moore, J., Trunet, P. F., Coombes, R. C., Powles, T. J., Rubens, R., and Smith, I. E. Endocrine changes with the aromatase inhibitor fadrozole hydrochloride in breast cancer. Eur. J. Cancer, 30A: 1453–1458. 29. Plourde, P. V., Dyroff, M., Dowsett, M., Demers, L., Yates, R., and Webster, A. Arimidex. A new oral, once-a-day aromatase inhibitor. J. Steroid. Biochem. Mol. Biol., 53: 175–179, 1995. 30. Walton, P. L., Yates, R. A., and Dukes, M. “Arimidex.” An overview of a new selective nonsteroidal aromatase inhibitor. In: M. Motta and M. Serio (eds.), Sex Hormones and Antihormones in EndocrineDependent Pathology: Basic and Clinical Aspects, pp. 311–316. Amsterdam: Elsevier Science Publishers, B. V., 1994. 31. Plourde, P. V., Dyroff, M., and Dukes, M. Arimidex. A potent and selective fourth-generation aromatase inhibitor. Breast Cancer Res. Treat., 30: 103–111, 1994. 32. Yates, R. A., Dowsett, M., Fisher, G. V., Selen, A., and Wyld, P. J. “Arimidex” (ZD1033): a selective, potent inhibitor of aromatase in postmenopausal female volunteers. Br. J. Cancer, 73: 543–548, 1996. 33. Wolter, J., Robert, N., Harvey, H., Berkowitz, I., and Plourde, P. V. “Arimidex” (ZD1033). A Phase I study of a new, selective orally active aromatase inhibitor in postmenopausal women with advanced breast cancer. Proc. Am. Soc. Clin. Oncol., 14: 119, 1995. 34. Iveson, T. J., Smith, I. E., Ahern, J., Smithers, D. A., Trunet, P. F., and Dowsett, M. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women. J. Clin. Endocrinol. Metab., 77: 324 –331, 1993. 35. Bhatnagar, A. S., Batzl, C., Häusler, A., Schieweck, K., Lang, M., and Trunet, P. F. Pharmacology of nonsteroidal aromatase inhibitors. In: J. R. Pasqualini and B. S. Katzenellenbogen (eds.), Hormone-dependent Cancer, pp. 155–168. New York: Marcel Dekker, Inc., 1996. 36. Bisagni, G., Cocconi, G., Scaglione, F., Fraschini, F., Pfister, C., and Trunet, P. F. Letrozole, a new oral nonsteroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study. Ann. Oncol., 7: 99 –102, 1996. 37. Iveson, T. J., Smith, I. E., Ahern, J., Smithers, D. A., Trunet, P. F., and Dowsett, M. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res., 53: 266 –270, 1993. 38. Lipton, A., Demers, L., Harvey, H. A., Kambic, K. B., Grossberg, H., Brady, C., Adlercruetz, H., Trunet, P. F., and Santen, R. J. Letrozole (CGS 20267). A Phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer (Phila.), 75: 2132–2138, 1995. 39. Bajetta, E., Zilembo, N., Dowsett, M., Guillevin, L., Di Leo, A., Celio, L., Martinetti, A., Marchianò, A., Pozzi, P., Stani, S., and Bichisao, E. Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur. J. Cancer, 35: 208 –213, 1999. 40. Goss, P. E., Clark, R. M., and Ambus, U. Phase II study of vorozole (R83842), a new aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression on tamoxifen. Clin. Cancer Res., 1: 287–294, 1995. 41. Paridaens, R., Piccart, M., and Nooij, M. Phase II study of vorozole (R83842), a new non-steroidal aromatase inhibitor, in advanced breast cancer. Eur. J. Cancer, 30A (Suppl. 2): 523, 1994. 42. Johnston, S. R. D., Smith, I. E., Doody, D., Jacobs, S., Robertshaw, H., and Dowsett, M. Clinical and endocrine effects of the oral aromatase inhibitor vorozole in postmenopausal patients with advanced breast cancer. Cancer Res., 54: 5875–5881, 1994. 43. Peréz-Carrión, R., Candel, V. A., Calabresi, F., Michel, R. T., Santos, R., Delozier, T., Goss, P. P., Mauriac, L., Feuilhade, F., Freue, M., Pannuti, F., van Belle, S., Martinez, J., Wehrle, E., and Royce, C. M. Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Ann. Oncol., 5 (Suppl. 7): S19 –S24, 1994. 44. Dowsett, M., Cunningham, D. C., Stein, R. C., Evans, S., Dehennin, L., Hedley, A., and Coombes, R. C. Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Cancer Res., 49: 1306 –1312, 1989. 45. Reed, M. J., Lai, L. C., Owen, A. M., Singh, A., Coldham, N. G., Purohit, A., Ghilchik, M. W., Shaikh, N. A., and James, V. H. Effect of treatment with 4-hydroxyandrostenedione on the peripheral conversion of androstenedione to estrone and in vitro tumor aromatase activity in postmenopausal women with breast cancer. Cancer Res., 50: 193–196, 1990. 46. Giudici, D., Ornati, G., Briatico, G., Buzzetti, F., Lombardi, P., and di Salle, E. 6-Methyleneandrosta-1, 4-diene-3, 17-dione (FCE 24304): a new irreversible aromatase inhibitor. J. Steroid. Biochem., 30: 391–394, 1988. 47. Geisler, J., King, N., Dowsett, M., Ottestad, L., Lundgren, S., Walton, P., Kormeset, P. O., and Lønning, P. E. Influence of anastrozole (“Arimidex”), a selective, nonsteroidal aromatase inhibitor, on in vivo aromatisation and plasma estrogen levels in post-menopausal women with breast cancer. Br. J. Cancer, 74: 1286 –1291, 1996. 48. Geisler, J., Anker, G., Dowsett, M., and Lønning, P. E. Letrozole suppresses estrogen levels in postmenopausal breast cancer patients more completely than anastrozole. Proc. Am. Soc. Clin. Oncol., 19: 102a, 2000. 49. Dowsett, M., Geisler, J., Haynes, B. P., Anker, G., and Lønning, P. E. Letrozole achieves more complete inhibition of whole body aromatisation than anastrozole. Eur. J. Cancer, 36 (Suppl. 5): S88, 2000. 50. Vorobiof, D. A., Kleeberg, U. R., Peréz-Carrión, R., Dodwell, D. J., Robertson, J. F. R., Calvo, L., Dowsett, M., and Clack, G. A. A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex) with intramuscular formestane in postmenopausal women with advanced breast cancer. Ann. Oncol., 10: 1219 –1225, 1999. 51. Coombes, R. C., Hughes, S. W., and Dowsett, M. 4-Hydroxyandrostenedione: a new treatment for postmenopausal patients with breast cancer. Eur. J. Cancer, 28A: 1941–1945, 1992. 52. Johannessen, D. C., Engan, T., di Salle, E., Zurlo, M. G., Paolini, J., Ornati, G., Piscitelli, G., Kvinnsland, S., and Lønning, P. E. 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., 3: 1101–1108, 1997. 53. Jones, S., Vogel, C., Arkhipov, A., Fehrenbacher, L., Eisenberg, P., Cooper, B., Honig, S., Polli, A., Whaley, F., and di Salle, E. Multicenter Phase II trial of exemestane as hormonal therapy of postmenopausal women with breast cancer. J. Clin. Oncol., 17: 3418 –3425, 1999. 54. Jonat, W., Howell, A., Blomqvist, C., Eiermann, W., Winblad, G., Tyrrell, C., Mauriac, L., Roche, H., Lundgren, S., Hellmund, R., and Azab, M. A randomised trial comparing two doses of the new selective aromatase inhibitor (“Arimidex”) with megestrol acetate in postmenopausal women with advanced breast cancer. Eur. J. Cancer, 32A: 404 – 412, 1996. 55. Buzdar, A. U., Jones, S. E., Vogel, C. L., Wolter, J., Plourde, P., and Webster, A., for the Arimidex Study Group. A Phase III trial comparing anastrozole (1 and 10mg), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast cancer. Cancer (Phila.), 79: 730 –739, 1997. 56. Howell, A. Clarification of anastrozole/megestrol acetate trial program design. J. Clin. Oncol., 18: 4109, 2000. 57. Hayward, J. L., Carbone, P. P., Heuson, J-C., Kumaoka, S., Segaloff, A., and Rubens, R. D. Assessment of response to therapy in advanced breast cancer. Cancer (Phila.), 39: 1289 –1294, 1977. 58. Buzdar, A., Jonat, W., Howell, A., Jones, S. E., Blomqvist, C., Vogel, C. L., Eiermann, W., Wolter, J. M., Azab, M., Webster, A., A., and Plourde, P. V., for the Arimidex Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two Phase III trials. J. Clin. Oncol., 14: 2000 –2011, 1996. Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. 2634 Aromatase Inhibition in Breast Cancer Treatment 59. Howell, A., Buzdar, A., and Jonat, W. Arimidex (anastrozole)— effective in advanced breast cancer (ABC) patients with visceral and liver metastases. Breast Cancer Res. Treat., 50: 304, 1998. 60. Robertson, J. F. R., Howell, A., Buzdar, A., von Euler, M., and Lee, D. Static disease on anastrozole provides similar benefit as objective response in patients with advanced breast cancer. Breast Cancer Res. Treat., 58: 157–162, 1999. 61. Dombernowsky, P., Smith, I., Falkson, G., Leonard, R., Panasci, L., Bellmunt, J., Gordin, G., Gudgeon, A., Morgan, M., Fornasiero, A., Hoffmann, W., Michel, J., Hatschek, T., Tjabbes, T., Chaudri, H. A., Harnberger, U., and Trunet, P. E. 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., 16: 453– 461, 1998. 62. Evaluation of the cancer patient and the response to treatment. In: S. Monfardini, K. Brunner, and D. Crowther (eds.), UICC—Manual of Adult and Paediatric Medical Oncology, pp. 22–38. Berlin: SpringerVerlag, 1987. 63. Chaudri, H. A., and Trunet, P. F. Letrozole. Updated duration of response. J. Clin. Oncol., 17: 3859 –3860, 1999. 64. Buzdar, A. U. Letrozole. Which dose to be used? J. Clin. Oncol., 18: 1802–1803, 2000. 65. Gershanovich, M., Chaudri, H. A., Campos, D., Lurie, H., Bonaventura, A., Jeffrey, M., Buzzi, F., Bodrogi, I., Ludwig, H., Reichardt, P., O’Higgins, N., Romieu, G., Friederich, P., and Lassus, M., for the Letrozole International Trial Group (AR/BC3). Letrozole, a new oral aromatase inhibitor: randomized trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann. Oncol., 9: 639 – 645, 1998. 66. Goss, P. E., Winer, E. P., Tannock, I. F., and Schwartz, L. H. Randomized Phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. J. Clin. Oncol., 17: 52– 63, 1999. 67. Houston, S. J., for the Rivizor Study Group. Rivizor versus aminoglutethimide (AG) in the second-line endocrine treatment of postmenopausal patients with advanced breast cancer (ABC) following tamoxifen failure. Breast, 6: 244 –245, 1997. 68. Bengtsson, N-O., Focan, C., Gudgeon, A., Illiger, H. J., Khayat, D., Murray, R., Nortier, J. W. R., Waxman, J., and Zielinski, C. A Phase III trial comparing vorozole (Rivizor) versus aminoglutethimide in the treatment of advanced postmenopausal breast cancer. Eur. J. Cancer, 33: S148, 1997. 69. Buzdar, A. U., Smith, R., Vogel, C., Bonomi, P., Keller, A. M., Favis, G., Mulagha, M., and Cooper, J. Fadrozole HCl (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma. Cancer (Phila.), 77: 2503–2513, 1996. 70. Freue, M., Kjaer, M., Boni, C., Joliver, J., Janicke, F., Willemse, P. H. B., Coombes, R. C., Van Belle, S., Pérez-Carrión, R., Zieschang, J., Ibarra de Palacios, P., and Rose, C. Open comparative trial of formestane versus megestrol acetate in postmenopausal patients with advanced breast cancer previously treated with tamoxifen. Breast, 9: 9 –16, 2000. 71. Kaufmann, M., Bajetta, E., Dirix, L. Y., Fein, L. E., Jones, S. E., Zilembo, N., Dugardyn, J-L., Nasurdi, C., Mennel, R. G., Cervek, J., Fowst, C., Polli, A., di Salle, E., Arkhipov, A., Piscitelli, G., Miller, L. L., and Massimini, G., 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 study. J. Clin. Oncol., 18: 1399 –1411, 2000. 72. Bonneterre, J., Thürlimann, B. J. K., and Robertson, J. F. R. 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., 18: 3748 –3757, 2000. 73. Nabholtz, J. M., Buzdar, A., Pollak, M., Harwin, W., Burton, G., Mangalik, M., Steinberg, M., Webster, A., and von Euler, M. 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., 18: 3758 –3767, 2000. 74. Nabholtz, J. M., Bonneterre, J., Buzdar, A. U., Thuerlimann, B. J. K., Robertson, J. F. R., Webster, A., Steinberg, M., and von Euler, M., on behalf of the “Arimidex” Study Group. Preliminary results of two multi-center trials comparing the efficacy and tolerability of “Arimidex” (anastrozole) and tamoxifen in postmenopausal women with advanced breast cancer. Breast Cancer Res. Treat., 57: 31, 1999. 75. Buzdar, A., Nabholtz, J. M., Robertson, J. F. R., Thürlimann, B., Bonneterre, J., von Euler, M., Steinberg, M., and Webster, A. Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer (ABC) in postmenopausal (PM) women— combined analysis of two identically designed multicenter trials. Proc. Am. Soc. Clin. Oncol., 19: 154a, 2000. 76. Milla-Santos, A., Milla, L., Rallo, L., and Solano, V. Anastrozole vs. tamoxifen in hormonodependent advanced breast cancer. A Phase II randomized trial. Breast Cancer Res. Treat., 64: 51, 2000. 77. Mouridsen, H., Peréz-Carrión, R., Becquart, D., Pluzanska, A., Chaudri, H., Dugan, M., and Staffler, B. Letrozole (Femara) versus tamoxifen: preliminary data of a first-line clinical trial in postmenopausal women with locally advanced or metastatic breast cancer. Eur. J. Cancer, 36 (Suppl. 5): S88, 2000. 78. Thürlimann, B., Beretta, K., Bacchi, M., Castiglione-Gertsch, M., Goldhirsch, A., Jungi, W. F., Cavalli, F., Senn, H-J., Fey, M., and Löhnert, T. First-line fadrozole HCl (CGS 16949A) versus tamoxifen in postmenopausal women with advanced breast cancer. Ann. Oncol., 7: 471– 479, 1996. 79. Paridaens, R., Dirix, L. Y., Beex, L., Nooij, M., Cufer, T., Lohrisch, L., Biganzoli, L., Van Hoorebeeck, I., Duchateau, L., Lobelle, J., and Piccart, M. 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., 19: 83a, 2000. 80. Hamilton, A., and Piccart, M. The third-generation nonsteroidal aromatase inhibitors: a review of their clinical benefits in the secondline hormonal treatment of advanced breast cancer. Ann. Oncol., 10: 377–384, 1999. 81. Goss, P. E. Risks versus benefits in the clinical application of aromatase inhibitors. Endocr. Relat. Cancer, 6: 325–332, 1999. 82. Goss, P. E., and Strasser, K. Aromatase inhibitors in the treatment and prevention of breast cancer. J. Clin. Oncol., 19: 881– 894, 2001. 83. Buzdar, A. U. Role of aromatase inhibitors in advanced breast cancer. Endocr. Relat. Cancer, 6: 219 –225, 1999. 84. Thürlimann, B., Paridaens, R., Serin, D., Bonneterre, J., Roche, H., Murray, R., Di Salle, E., Lanzalone, S., Zurlo, M. G., and Piscitelli, G. Study Group. Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on aminoglutethimide: a Phase II multicentre, multinational study. Eur. J. Cancer, 33: 1767–1773, 1997. 85. Höffken, K., Jonat, W., Possinger, K., Kolbel, M., Kunz, T., Wagner, H., Becher, R., Callies, R., Friederich, P., and Willmanns, W. Aromatase inhibition with 4-hydroxyandrostenedione in the treatment of postmenopausal patients with advanced breast cancer: a Phase II study. J. Clin. Oncol., 8: 875– 880, 1990. 86. Dixon, M. J., Renshaw, C., Bellamy, D. A., Cameron, D. A., and Miller, W. R. “Arimidex” as neoadjuvant therapy causes large reductions in tumor volume in postmenopausal women with large operable breast cancers. Proc. Am. Soc. Clin. Oncol., 18: 92a, 1999. 87. Miller, W. R., Dixon, J. M., Grattage, L., Stuart, M., and HoctinBoes, G. Effects of neoadjuvant treatment with the aromatase inhibitor, anastrozole (“Arimidex”) on peripheral and in situ estrogen synthesis and uptake by breast tissue in postmenopausal women. Breast Cancer Res. Treat., 57: 32, 1999. 88. Geisler, J., Berntsen, L., Ottestad, L., Lindtjoern, B., Dowsett, M., and Lønning, P. E. Comparison of the effects of neoadjuvant “Arimi- Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Clinical Cancer Research 2635 dex” (anastrozole) on plasma and intratumor tissue estrogen levels in postmenopausal breast cancer patients. Breast, 8: 241, 1999. 89. Miller, W. R., Telford, J., Love, C., Leonard, R. C. F., Hillier, S., Gundacker, H., Smith, H., and Dixon, J. M. Effects of letrozole as primary medical therapy on in situ estrogen synthesis and endogenous levels within the breast. Breast, 7: 273–276, 1998. 90. Dixon, J. M., Love, C. D. B., Tucker, C., Bellamy, C., Leonard, R. C. F., and Miller, W. R. Letrozole as primary medical therapy for locally advanced and large operable breast cancer. Eur. J. Cancer, 34 (Suppl. 5): S13, 1998. 91. Paepke, S., Apffelstaedt, J., Eremin, J., Mauriac, L., Semiglazov, V., Chaudri, H. A., and Borgs, M. Neo-adjuvant treatment of postmenopausal breast cancer patients with letrozole (Femara): a randomized study versus tamoxifen. Eur. J. Cancer, 36 (Suppl. 5): S76, 2000. 92. Baum, M. Use of aromatase inhibitors in the adjuvant treatment of breast cancer. Endocr. Relat. Cancer, 6: 231–234, 1999. 93. Baum, M., and Houghton, J., on behalf of the ATAC Steering Committee, UK 1998. “Arimidex,” tamoxifen alone or in combination (ATAC) adjuvant trial in post-menopausal breast cancer. Eur. J. Cancer, 34 (Suppl. 1): S39, 1998. 94. Lønning, P. E. Aromatase inhibitors and their future role in postmenopausal women with early breast cancer. Br. J. Cancer, 78 (Suppl. 4): 12–15, 1998. 95. Piccart, M. J., and Goldhirsch, A., on behalf of the Breast International Group. In: L. Biganzoli and C. Straehle (eds.), An Overview of Recent and Ongoing Adjuvant Clinical Trials for Breast Cancer, Ed. 2. Belgium: Moreau PCE s.a., 2000. 96. Harper-Wynne, C., and Coombes, R. C. Anastrozole shows evidence of activity in postmenopausal patients who responded or stabilised on formestane therapy. Eur. J. Cancer, 35: 744 –746, 1999. 97. Lønning, P. E., Bajetta, E., Murray, R., Tubiana-Hulin, M., Eisenberg, P. D., Mickiewicz, E., Celio, L., Pitt, P., Mita, M., Aaronson, N. K., Fowst, C., Arkhipov, A., di Salle, E., Polli, A., and Massimini, G. Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a Phase II trial. J. Clin. Oncol., 18: 2234 –2244, 2000. Downloaded from clincancerres.aacrjournals.org on May 15, 2017. © 2001 American Association for Cancer Research. Advances in Aromatase Inhibition: Clinical Efficacy and Tolerability in the Treatment of Breast Cancer Aman Buzdar and Anthony Howell Clin Cancer Res 2001;7:2620-2635. Updated version Cited articles Citing articles E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/7/9/2620 This article cites 73 articles, 29 of which you can access for free at: http://clincancerres.aacrjournals.org/content/7/9/2620.full.html#ref-list-1 This article has been cited by 9 HighWire-hosted articles. Access the articles at: /content/7/9/2620.full.html#related-urls Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. 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