Sequencing of hormonal therapy in postmenopausal women with metastatic breast cancer

Sequencing of hormonal therapy in postmenopausal women with metastatic breast cancer

CLINICAL THERAPEUTICS®/VOL. 24, SUPPL. C, 2002 Sequencing of Hormonal Therapy in Postmenopausal Women with Metastatic Breast Cancer Leroy Monroe Park...

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CLINICAL THERAPEUTICS®/VOL. 24, SUPPL. C, 2002

Sequencing of Hormonal Therapy in Postmenopausal Women with Metastatic Breast Cancer Leroy Monroe Parker, MD Department of Medicine, Harvard Medical School, The Dana-Farber Cancer Institute, Boston, Massachusetts

ABSTRACT

Background: Hormonal therapy (HT) is an important consideration in the management of postmenopausal women with metastatic breast cancer. Despite the fact that the advanced-stage disease is virtually incurable, HTs can offer patients disease control equivalent to that of chemotherapy, but with improved quality of life (QOL). Knowledge of the estrogen and progesterone receptor status, as well as other clinical factors, allows for selection of patients who are most likely to benefit from HT. Disease that becomes refractory to an initial HT may respond to another agent or class of HTs. Thus, HTs are generally administered sequentially, delaying the need for cytotoxic chemotherapy, which often reduces QOL. Optimal sequencing is thus one of the more important facets of HT. Prior to the release of a number of newer agents, tamoxifen had been considered as initial HT. At present, more agents exist, including the aromatase inhibitors, progestins, and the estrogen receptor antagonist fulvestrant. Objective: This article reviews key trials evaluating the use of sequential HTs. Methods: Articles were identified for inclusion in this manuscript through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182, 780. Results: Results of Phase III studies have shown many of these agents to be equivalent or superior to tamoxifen and can be used initially to treat patients who either have failed tamoxifen therapy or may be unable to tolerate some of the toxicities associated with taAccepted for publication April 2, 2002. Printed in the USA. Reproduction in whole or part is not permitted.

0149-2918/02/$19.00

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moxifen. For example, the aromatase inhibitors have been shown to be highly active and tolerable in postmenopausal women with breast cancer who have failed tamoxifen therapy or who are naive to HT. Other clinical trials have demonstrated the efficacy of fulvestrant in patients with metastatic breast cancer who are tamoxifen-resistant, and have shown fulvestrant to be at least as effective as anastrozole in tamoxifen-resistant patients. Conclusions: Although the optimum sequence of HTs remains controversial, using the newer agents as initial or subsequent therapy should improve QOL and may improve overall survival. Key words: sequencing hormonal therapies, metastatic breast cancer, aromatase inhibitors, tamoxifen, estrogen receptor antagonists. (Clin Ther. 2002;24[Suppl C]: C43-C57) INTRODUCTION Our biological understanding of receptor activity has expanded over the past several decades, allowing a variety of hormonal agents to be designed for the treatment of MBC in postmenopausal women. This has provided a therapeutic opportunity for these patients who would otherwise turn to more toxic chemotherapy or have no options whatsoever, except for palliative care. Now the focus is on the proper sequencing of these drugs so that survival time is maximized. The mechanism of action by which hormonal therapies (HTs) work in postmenopausal patients with metastatic breast cancer (MBC) has expanded in the past 3 decades, with the introduction of the first-generation selective estrogen receptor modulator (SERM) tamoxifen 1 and the first-generation aromatase inhibitor C44

(AI) aminoglutethimide. 2 At that point, the era of contemporary HT began, and many postmenopausal women with advanced carcinoma of the breast were given other therapeutic options besides invasive, ablative endocrine therapy, notably adrenalectomy and hypophysectomy, which had been in use for the prior 2 decades. Subsequently, several major advances have pushed HT into the forefront of therapeutic options for patients with MBC. First, the demonstration of estrogen receptors (ERs) 3 and progesterone receptors (PgRs) 4 in breast tumors has provided a rationale for the development of compounds that could be used to control tumors hormonally. It is now known that the presence of breast tumor cells rich in ERs and PgRs is the most important factor in predicting response to HT. In patients with ER-positive and PgR-positive tumors, 50% to 70% respond to HT. 4 Of patients who have tumors that are positive for only 1 receptor, 33% respond to HT. 4 If both receptors are negative, responses are -10%. Menopausal status is another important dynamic linked to these receptors: 63% of postmenopausal women with breast cancer have ERs and PgRs in their tumor cells, compared with 25% to 45% of premenopausal women. 5 Second, HT offers a finite degree of control in an otherwise incurable illness. A meta-analysis of long-term follow-up resuits from randomized trials has confirmed that HT appreciably improves relapse-free and overall survival while reducing the incidence of contralateral breast disease. 6 More recent information suggests a promising role for the SERMs as preventive agents against carcinoma of the breast. 7'8 Third, many HT agents with different mechanisms of action (Table I) are active in postmenopausal MBC. 9 In addition to

L.M. PARKER

Table I. Mechanisms of action for hormonal therapies in postmenopausal women. 9 Hormonal Therapy

Mechanism of Action

SERMs Binds to ERs, preventing binding of estrogen to the receptor ER antagonists Binds to ERs, causing ER downregulation of ER protein Aromatase inhibitors Inhibits the aromatase enzyme, which converts androgens to estrogens, reducing estrogen levels and estrogenic activity Progestins Binds to PgRs, reducing ERs and estrogenic activity Adrenalectomy Eliminates the peripheral estrogen source (ie, conversion of androgens to estrogen) by eliminating the source of androgen production Reduces ACTH, FSH, and LH, and subsequently inhibits production of Hypophysectomy adrenal androgens, estrogen, and progesterone Binds to ERs, reducing estrogenic activity Estrogens Suppresses FSH and LH, thus reducing estrogen production, and occupies Androgens androgen receptors, leading to a reduction in ERs and estrogenic activity SERM = selectiveestrogen receptor modulator; ER = estrogen receptor; PgR = progesteronereceptor; ACTH = adrenocorticotropichormone;FSH = follicle-stimulatinghormone;LH = luteinizinghormone.

SERMs and AIs, progestins, androgens, estrogens, and ER antagonists also are available, thereby providing clinicians with an armamentarium of therapeutic alternatives. Fourth, a partial lack of cross-resistance exists between different HTs. l° Thus, a patient with a hormone-sensitive tumor who has acquired resistance following an initial response to therapy may respond to other alternate HT. 11-14 Now that research has extended the options for HT of breast cancer, the next quest is to determine the best sequencing of these agents. Thus, in optimizing sequential HT, the selection of the individual modalities in the appropriate order is crucial to achieving the maximum duration of disease control.

METHODS Articles were identified for inclusion in this manuscript through the following

searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, hormonal thera-

pies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and IC1182, 780. SEQUENCING HORMONAL THERAPY For patients with receptor-positive breast cancer, HT is essential to the overall treatment plan. In addition to causing fewer adverse effects than chemotherapy, HTs are more efficacious when used sequentially and offer patients improved quality of life (QOL) in situations that might otherwise be without options. 15,16 An early study demonstrated that patients who relapsed from an endocrine ablative surgiC45

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cal procedure (hypophysectomy) showed a response when tamoxifen was used as second-line therapy. 15 These results imply that the mechanism of action of tamoxifen directly affects the tumor through binding to ERs rather than through the pituitary-gonadal axis or adrenal-gonadal axis, as is seen in hypophysectomy and adrenalectomy, respectively. 15 Tumors that initially respond to one type of HT can become refractory to that particular agent or class but may respond to another agent or class.17 Therefore, HTs are generally administered sequentially, with subsequent agents offered as resistance develops and the disease advances. Typically, interclass sequencing is preferable to intraclass sequencing principally for reasons of resistance. For example, tamoxifen and toremifene, both SERMs, have been shown to be clinically crossresistant in patients with advanced breast cancer. 18,19

The order of sequencing is considered the most controversial area in treating breast cancer with HT. 2° A recent multivariate analysis 16 of different HTs used in sequence (antiestrogens, progestins, luteinizing hormone-releasing hormone agonists, and AIs) and objective response (OR) rates (complete response [CR] + partial response [PR]) showed that the choice of initial HT does not influence the overall efficacy of the subsequent HT (Table 11).16 In this analysis, the OR rates to initial and subsequent HTs were similar: 42.7% and 42.5%, respectively. If disease stabilization of >6 months is taken into account, the clinical benefit rate (CR + PR + stable disease [SD] >24 weeks) was 65.6% for initial treatment and 52.5% for subsequent treatment. Thus, although moving to subsequent therapy offers a somewhat smaller likelihood of response, the ability to select another HT gives both patients and physicians more options.

Table II. Number (%) of responses of initial and subsequent therapies in patients with recurrent breast cancer. 16 Therapy Patients who received an antiestrogen as initial therapy (n = 20) Patients who produced an OR to the antiestrogen Patients who produced an OR to any subsequent therapy Patients who produced an OR to the antiestrogen as initial therapy and who responded to any subsequent therapy Patients who received an aromatase inhibitor as initial therapy (n = 15) Patients who produced an OR to the aromatase inhibitor Patients who produced an OR to any subsequent therapy Patients who produced an OR to the aromatase inhibitor as initial therapy and who responded to any subsequent therapy Patients who received an LHRH agonist as initial therapy (n = 3) Patients who produced an OR to the LHRH agonist Patients who produced an OR to any subsequent therapy OR = objective response; LHRH = luteinizing hormone-releasing hormone.

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Response

6 (30.0) 9 (45.0) 3 (50.0) 8 (53.3) 4 (26.7) 4 (50.0)

3 (100.0) 3 (100.0)

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INITIAL HORMONAL THERAPIES FOR METASTATIC BREAST CANCER The selection of an agent for use in sequencing HT is based on clinical practice and evolves as new data become available. For example, tamoxifen, the most widely used HT for breast cancer, was originally approved for and used in the treatment of MBC; its effectiveness as MBC therapy led to its evaluation and use as adjuvant and preventive therapy for breast cancer. (Dr. Cummings offers an insightful overview of evolving uses of HT in this supplement.) Similarly, as new agents are developed, evaluated, and compared with existing therapy, the sequential order of HT changes. As with most therapies, efficacy is the primary criterion for selecting agents as initial and subsequent HT in MBC, although safety, both acute and long term, is also important. Most commonly, HTs with a prolonged survival time are chosen over agents with a reduced survival time. In the event that survival times are similar among agents, those with a higher res p o n s e - b o t h objective response and clinical benefit--are selected first as long as toxicity is not greatly increased. Decreased toxicity usually translates into a better QOL and may also improve compliance, thereby improving overall treatment response. Thus, when 2 treatments are shown to be equally efficacious, the selection of one agent over another is based on their toxicity profiles. For many years, tamoxifen has been the standard first-line HT for patients with MBC and hormone receptor-positive disease. All newer HTs are compared with tamoxifen, with the goals of increased survival and/or improved QOL. Megestrol

acetate (MA) was the standard therapy used after tamoxifen failure. Thus, secondline efficacy of many of the newer agents, such as AIs, was shown in clinical trials comparing these agents with MA.

Tamoxifen The use of tamoxifen has resulted in a substantial modification of the natural history of breast cancer, particularly in postmenopausal women. Tarnoxifen improves overall survival rates while also reducing the incidence of contralateral breast disease. 6 More recent information suggests a promising role for tamoxifen as a preventive agent against carcinoma of the breast. 7,8 As such, tamoxifen remains the current adjuvant HT of choice of several organizations, including the National Institutes of Health, National Comprehensive Cancer Network (NCCN), Early Breast Cancer Trialists' Collaborative Group (EBCTCG), and the St. Gallen International Consensus panel. 6,21-e3 Overall, ~30% of women with MBC treated with tamoxifen have objective regression of the tumor for an average of 12 months, and in an additional 20%, the disease remains stable for at least 6 months. 24 Approximately 50% of all women with ER-positive tumors receive some benefit from tamoxifen, compared with <10% of women with tumors in whom no ERs are detected.24 A few women have remissions lasting >5 years, but resistance to tamoxifen inevitably develops, necessitating the sequencing of other appropriate HTs. 24

Aromatase Inhibitors AIs have been used effectively for many years as alternate HT for advanced breast cancer in postmenopausal women who C47

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fail initial HT. Aminoglutethimide, a firstgeneration AI, produces an objective response rate comparable to those observed with tamoxifen. 5,25 The nonselective action of aminoglutethimide produces significant toxicities (eg, rash, orthostatic hypotension) and requires the use of corticosteroids to maintain normal levels of cortisol, thereby limiting its potential as a first-line HT for MBC.5,26 Thus, aminoglutethimide was considered an appropriate alternative HT after tamoxifen failure for MBC until newer AIs with significantly better toxicity profiles became available. The newer, selective AIs anastrozole, exemestane, and letrozole also have been shown to be effective HTs for postmenopausal women with MBC who have failed tamoxifen therapy. They also have superior toxicity profiles compared with that of MA in randomized trials (see section titled "Progestins vs Aromatase

Inhibitors"). Consequently, these drugs have replaced progestins as standard HT for MBC following failure with tamoxifen therapy. 27-29 A series of recent studies compared AIs, such as anastrozole and letrozole, with tamoxifen as initial therapy in patients with advanced breast cancer. The results of these studies have led to a consideration of changes in the optimal sequencing of HTs. To illustrate, 2 randomized, double-blind, multicenter studies comparing anastrozole (1 mg/d) with tamoxifen (20 mg/d) in 1021 patients with advanced breast cancer revealed that anastrozole was as effective as tamoxifen in objective response, clinical benefit, and time to disease progression (TTP); survival data were immature at the time of publication (Table 111).30 Anastrozole, however, was superior to tamoxifen in terms of median TTP in patients with estrogen- or proges-

Table III. Efficacy of anastrozole and tamoxifen in the initial treatment of advanced breast cancer (N = 1021).

Outcome Parameter OR, %* Clinical benefit, %t CR, % PR, % SD >24 weeks, % SD <24 weeks, % Progression, % Median TTP, mo*

Anastrozole 1 mg (n = 511) 29.0 57.1 4.7 24.3 28.2 3.1 39.7 8.5

Tamoxifen 20 mg (n = 510) 27.1 52.0 4.1 22.9 24.9 2.4 45.7 7.0

Adapted with permission.3° OR = objective response; CR = complete response; PR = partial response; SD = stable disease; TrP = time to progression. *Complete response + partial response. tComplete response + partial response + stable disease >24 weeks. Hn patients with estrogen receptor- or progesterone receptor-positivedisease, median TIP was 10.7 months in anastrozole-treated patients and 6.4 months in tamoxifen-treatedpatients; P = 0.022. C48

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terone-positive disease when analyzed retrospectively (10.7 and 6.4 months, respectively; P = 0.022). 30 Both drugs were well tolerated, although compared with anastrozole, patients receiving tamoxifen experienced more thromboembolic events (6.5% vs 3.6%; P = 0.043) and vaginal bleeding (2.2% vs 1.0%; P = NS). 3° A study of 907 postmenopausal women with hormone receptor-positive or receptorunknown MBC that compared letrozole with tamoxifen as initial therapy showed that clinical benefit rate (49% vs 38%; P = 0.001) and TTP (41 weeks vs 26 weeks; P = 0.001) were significantly higher with letrozole than with tamoxifen, and letrozole reduced the risk of disease progression by 30% (P = 0.0001). 31 The safety profile of the 2 drugs was quite similar. The most common adverse effects with suspected causality for letrozole and tamoxifen, respectively, were hot flashes (16% vs 13%), nausea (6% vs 6%), and hair thinning (5% vs 3%). Thromboembolic events, irrespective of drug relationship, occurred in 1% of letrozole-treated patients and in 2% of tamoxifen-treated patients. The incidence of vaginal bleeding was not reported for either drug in this study. With the data from trials evaluating AIs as initial therapy becoming available, the optimal sequencing of HT has evolved. AIs would now seem to qualify as initial therapy in postmenopausal women with advanced ER-positive or ERunknown breast cancer and are now recommended by the NCCN as an appropriate option in the initial treatment of postmenopausal women with MBC who are antiestrogen-naive or who have not been exposed to antiestrogen therapy for >1 year. 22 AIs may replace tamoxifen as the standard initial HT because of their

greater efficacy and safety profile if longterm results maintain the trends; however, studies comparing the AIs to one another are needed to determine whether any AI is preferred over another AI.

SEQUENCING OPTIONS BEYOND TAMOXIFEN AND AROMATASE INHIBITORS Although tamoxifen and AIs are effective HTs in the treatment of MBC, some patients will develop resistance to these agents and require subsequent therapies at the time of progression. Additional therapies such as progestins, estrogens, and androgens have documented efficacy in postmenopausal women with MBC but have been relegated to third- or higher-line therapies because of their significant toxicities. 5 Fulvestrant, an ER antagonist, is less toxic than these agents and also may be an effective option. 32

Progestins MA and medroxyprogesterone acetate (MPA) are the most widely used progestins in treating MBC. Both display OR rates similar to those obtained with tamoxifen in patients with advanced breast cancer. 4,33 In a study that compared MA 160 mg/d to MPA 1000 rag/d, OR rates and response duration were equivalent in both groups--OR rates were 25% and 30% for MA and MPA, respectively; response duration for MA and MPA was 14.0+ months (CR) and 9.8 months (PR) and 7.5+ months (CR) and 8.2+ months (PR), respectively. 34 Studies have compared these progestins with tamoxifen or AIs to assess their relative efficacy in MBC, although the study results of MA and MPA are not directly comparable. C49

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Progestins vs Tamoxifen In a study of 166 patients with recurrent or MBC, high-dose progestin therapy (MPA 1000 mg/d) produced an OR rate that was superior to that of tamoxifen (20 mg/d), but survival times were not longer and toxicity was greater. 35 The OR rates for MPA and tamoxifen were 34% and 17%, respectively (P--0.01). Patients with bone and liver metastases had a considerably higher PR rate with MPA compared with tamoxifen (33% vs 13% and 50% vs 8%, respectively; P < 0.05). The benefit observed in patients with bone metastases, which were present in the majority of patients (tamoxifen, 77%; MPA, 73%), accounts for the major differences in response between the 2 regimens. Median time to treatment failure (TTF) was 5.5 months for tamoxifen and 6.3 months for MPA (P -- NS). The median survival time (MST) was 33 months for MPA and 24 months for tamoxifen (P = NS). Both agents were associated with minimal toxicity, but 35% of patients receiving MPA gained >9 kg as opposed to only 2% of patients receiving tamoxifen. Nausea and vomiting were significantly more prevalent in patients receiving tamoxifen than in patients receiving MPA (mild plus moderate to severe, 29% vs 12%, respectively, P < 0.001). A randomized Phase III crossover study of 139 perimenopausal and postmenopausal women with advanced or recurrent breast cancer compared tamoxifen with MA as first-line H T . 36 The OR rate with MA (25%) was not significantly different from that produced by tamoxifen (33%) (P - NS). TTF also varied, albeit without statistical significance, between the 2 groups: MA, 9 months; tamoxifen, 12 months. Crossover treatment was given C50

on disease progression in 76 cases. Crossover response (OR) was seen in 3 (9%) of 35 patients receiving MA as second-line therapy and in 6 (15%) of 41 patients receiving tamoxifen as second-line HT. No significant difference was noted in survival rates between the groups, with MSTs of 24 and 32 months for the MA and tamoxifen groups, respectively. The toxicity profiles of the drugs were different, although significant toxicity was rare with either agent; mild to very severe edema was observed in 26% of the MAtreated patients compared with only 7% of the tamoxifen-treated patients. Mild to very severe hyperglycemia was noted in 10% of the MA-treated patients compared with none of the tamoxifen-treated patients. Mild to moderate hot flashes were seen in 2% of patients on MA compared with 29% of tamoxifen-treated patients. Based on these results, progestins such as MPA and MA appear to be logical choices both for patients who find the adverse reactions of tamoxifen unacceptable and for those who relapse on tamoxifen but who may benefit from further HT. Progestins vs Aromatase Inhibitors

Older studies comparing MA or MPA with aminoglutethimide as second-line therapy 12,37 showed that the progestins fared as well as the AI in objective responses in patients with advanced breast cancer. However, patients who received the aminoglutethimide appeared to have an enhanced QOL compared with patients who received MPA, which was associated with thrombophlebitis (P = 0.00 l) and hypertension (P = 0 . 0 0 2 ) . 12 Results of studies assessing the newer agents showed similar trends. 27-29 In 2 randomized, parallel-group, multicenter

L.M. PARKER

trials involving 764 patients with advanced breast cancer, patients received either anastrozole 1 or 10 mg/d or MA 40 mg QID. 27 Anastrozole 1 mg/d demonstrated a statistically significant survival advantage over MA (P < 0.025). Anastrozole 1 mg/d also had a longer median time to death (26.7 months) compared with MA (22.5 months). The 10-mg anastrozole group also demonstrated a survival benefit over the MA group (P = NS). Higher 2-year survival rates were observed for both anastrozole treatment groups (1 mg/d, 56.1%; 10 mg/d, 54.6%) compared with the MA group (46.3%). All 3 treatments were well tolerated, with some patients withdrawing from therapy because of an adverse reaction in the MA group (4.0%), anastrozole 1 mg group (1.9%), and anastrozole 10 mg group (2.8%). No deaths were noted in the groups receiving the AI; however, 2 deaths (0.8%) were reported in the MA group, 1 from stroke and another from pulmonary embolism. Letrozole (2.5 mg/d) also has been shown to be more effective and better tolerated than MA (160 mg/d) as HT in postmenopausal women with MBC who failed initial HT. 2s In a Phase III clinical trial comparing these 2 drugs, OR rates were significantly higher in patients receiving letrozole (23.6%) compared with patients receiving MA (16.4%; P = 0.04). 28 In addition, TTF was significantly prolonged in patients receiving letrozole (5.1 months vs 3.9 months; P = 0 . 0 4 ) . 28 Survival times and clinical benefit rates were similar between the 2 drugs. Severe adverse effects and treatment discontinuation due to toxicity were more common among patients receiving MA than among those receiving letrozole (95% CI, 11% to 27%). 28 Kaufmann et a129 demonstrated the superior activity and safety profile of

exemestane (25 mg/d) compared with MA (160 mg/d) as HT for postmenopausal women with MBC who had failed initial HT. Although OR rates were similar in patients receiving exemestane and MA (15.0% vs 12.4%), MSTs (not reached vs 123.4 weeks; P = 0.039), median TTP (20.3 weeks vs 16.6 weeks; P = 0.037), and median TTF (16.3 weeks vs 15.7 weeks; P = 0.042) were significantly longer with exemestane compared with MA. 29 Toxicity was similar between the 2 treatment groups; however, more exemestane-treated patients had improvement in pain scores, treatment-related signs and symptoms, and QOL. 29 Given their favorable side-effect profiles, QD dosing, and evidence of clinically relevant benefit, the AIs are considered equivalent in efficacy to MA given QID, but with an improved safety profile and QOL. Therefore, progestins should be considered an option after AI failure in postmenopausal women with advanced breast cancer.

Fulvestrant: An Estrogen Receptor Antagonist Fulvestrant, an ER antagonist without agonist activity, was developed to have the same antiestrogenic activity in breast tissue as SERMs such as tamoxifen, but without estrogenic activity on the endometrium or other tissues. Researchers hoped to provide a therapy as effective as or superior to tamoxifen, and better tolerated. 38 Phase II clinical trials have demonstrated its efficacy for postmenopausal patients with MBC who have failed initial tamoxifen therapy, and confirmed the lack of endometrial tissue thickening during treatment with the agent. 32,38 Unlike previous clinical trials that evaluated subsequent HT for MBC in patients who failed C51

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for nonresponders as zero) was significantly greater for fulvestrant than for anastrozole both in the European trial (27% greater, P = 0.01) and the North American trial (35% greater, P < 0.01). 39 Both drugs had similar safety profiles and were well tolerated. The most common adverse reactions were gastrointestinal disorders (46.3% vs 43.7%) and hot flashes (21.0% vs 20.6%) for fulvestrant and anastrozole, respectively (P = NS). Significantly more joint disorders were reported in patients receiving anastrozole than in patients receiving fulvestrant (10.6% vs 5.4%; P = 0.004). Although fulvestrant is the first commercially available injectable HT, complications such as injection-site pain or reactions were mild to moderate and led to treatment withdrawals in only 0.5% of patients. The rates of overall withdrawals due to a drug-related adverse event were 0.9% for fulvestrant and 1.2% for anastrozole. No evidence of endometrial tissue changes has been reported with fulvestrant or anastrozole. Fulvestrant has been shown to be at least as effective as

initial HT, anastrozole, rather than MA, was used as the comparative agent in Phase HI clinical trials evaluating fulvestrant because, at the time these studies were initiated, anastrozole had largely replaced M A as the HT of choice after tamoxifen failure in the treatment of MBC in postmenopausal women. Two Phase III, randomized, multicenter trials, 1 in Europe and 1 in North America, compared the efficacy and safety of fulvestrant (250 mg once a month by intramuscular injection) with those of anastrozole (1 mg/d orally) in 851 postmenopausal women with advanced breast cancer who developed progressive disease with prior tamoxifen therapy. 38 The primary end point was TTP; secondary end points were OR rate, duration of response (DOR), and safety. Efficacy end points are listed in Table IV. Overall, fulvestrant was at least as effective as anastrozole in terms of TTP, OR rate, and clinical benefit in both studies. 38 The mean DOR (defined for responders as the time from onset of response to disease progression and

Table IV. Comparison of fulvestrant and anastrozole in postmenopausal women with metastatic breast cancer who failed tamoxifen therapy. European Study

Clinical End Points Median TTE d OR, %* Clinical benefit, %t Median DOR in responders, mo

North American Study

Fulvestrant (n = 222)

Anastrozole (n = 229)

Fulvestrant (n = 206)

Anastrozole (n = 194)

166 20.3 44.6 14.3

156 14.9 45.0 14.0

165 17.0 43.7 19.3

103 17.0 36.1 10.5

Adapted with permission.38 TTP = time to progression; OR = objective response; DOR = duration of response. *Complete response + partial response. ¢Complete response + partial response + stable disease >24 weeks.

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anastrozole in postmenopausal women with advanced breast cancer, which is noteworthy because most patients had prior tamoxifen treatment. Retrospective data from the 2 aforementioned studies are available for 55 patients who failed tamoxifen therapy, responded to fulvestrant, and have since experienced disease progression. Fortythree of these patients (78%) were treated with subsequent HT: anastrozole (33 patients), letrozole (6 patients), MA (4 patients). 4° Of these 43 patients, 3 (7%) achieved a PR, 14 (33%) had SD for >24 weeks, and 26 (60%) had disease progression. Of the 39 patients (91%) receiving AIs, 3 (8%) achieved a PR, 12 (31%) had SD for >24 weeks, and 24 (62%) had disease progression. These resuits show that subsequent HT was effective in some patients following fulvestrant treatment and provide evidence that may affect how clinicians will sequence HTs in MBC. Overall, these trial results support the conclusion that fulvestrant is a valuable, new treatment option for postmenopausal women with endocrine-responsive advanced breast cancer after tamoxifen failure. Because of fulvestrant's similar efficacy and safety profile compared with anastrozole, ongoing studies are evaluating the role of fulvestrant as initial HT in the treatment of postmenopausal MBC. 38

Estrogens and Androgens Although estrogens and androgens have been used in the treatment of MBC, toxicity associated with their use in postmenopausal patients with breast cancer appears to be a major factor. For example, in trials that compared tamoxifen with either the estrogen diethylstilbestrol (DES)

or ethinyl estradiol (EE), treatment with estrogens had to be discontinued in ~50% of patients. 41,42 In addition, the OR rates of the estrogens were much lower than that of tamoxifen: DES vs tamoxifen, 22% vs 31%42; EE versus tamoxifen, 25% vs 53%. 41 A study that used a relatively low dose of DES (3 mg/d)43 showed a treatmentdiscontinuation rate of 15% in patients using the estrogen despite the fact that the OR rate of DES was slightly higher than that of tamoxifen (31% vs 28%). A trial that compared the androgen fluoxymesterone with tamoxifen 44 showed that the response to the first course of treatment was 30% with tamoxifen and 19% with fluoxymesterone, both administered as the first course of treatment. A longer survival time was seen in the tamoxifen group (P < 0.05), as well as a significantly longer TTP (P = 0.003). More liver toxicity (evidenced by transient increases in enzyme levels) and much higher degrees of hoarseness and hirsutism were noted in the fluoxymesterone group. Overall, the estrogens and androgens, if used at all, are relegated to the end stages of HT because of their significant toxicity, particularly in relation to the newer agents at the clinician's disposal. CONCLUSIONS The optimal sequencing of hormonal agents used in the treatment of postmenopausal breast cancer remains to be defined, but several facts are known. Some AIs have been shown to be as effective as tamoxifen as initial therapy in terms of objective response and with fewer side effects. In separate clinical trials, fulvestrant has demonstrated its value against anastrozole. The progestins, principally C53

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MA, are also effective in treating advanced breast cancer; however, with the greater efficacy of the newer agents and some of the cardiovascular complications associated with the progestins, these agents, although once considered second line, are now better as third- or fourth-line therapies. Based on knowledge of the randomized trials of HTs for MBC, recommended sequences of these therapies in postmenopausal women are presented in the Figure. Initial therapies could include either tamoxifen or an AI. If progression occurs with tamoxifen, an AI or fulvestrant could be used; if progression occurs with an AI, tamoxifen or fulvestrant could be used. Subsequent therapies should favor 1 of the 3 aforementioned therapies that have not yet been used in a particular patient's treatment. Following these, MA may be considered.

REFERENCES 1. Cole MP, Jones CT, Todd ID. A new antioestrogenic agent in late breast cancer: An early clinical appraisal of ICI46474. Br J Cancer. 1971;25:270-275. 2. Cash R, Brough AJ, Cohen MN, Satoh PS. Aminoglutethimide (Elipten-Ciba) as an inhibitor of adrenal steroidogenesis: Mechanism of action and therapeutic trial. J Clin Endocrinol Metab. 1967;27:12391248. 3. Jensen EV, Jacobson HI. Basic guides to the mechanism of estrogen action. Recent Prog Horm Res. 1962;18:387-414. 4. Sedlacek SM, Horwitz KB. The role of progestins and progesterone receptors in the treatment of breast cancer. Steroids. 1984;44:467-484. 5. Buzdar AU. Endocrine therapy in the treatment of metastatic breast cancer. Semin Oncol. 2001 ;28:291-304.

Tamoxifen

Initial

AI

Next

Fulvestrant

AI

Next

AI

Fulvestrant

Next

MA

MA

OR

Fulvestrant

Tamoxifen

Tamoxifen

Fulvestrant

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MA

Figure. Suggested sequences of hormonal therapies for postmenopausal patients with hormone receptor-positive advanced breast cancer. AI = aromatase inhibitor; M A = megestrol acetate. C54

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Address correspondence to:

Leroy Monroe Parker, MD, Department of Medicine, Harvard Medical School, The Dana-Farber Cancer Institute, 44 Binney Street #D1210, Boston, M A 02115-6013. E-mail: [email protected]

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