Hormonal Therapy for Advanced Breast Cancer

Hematol Oncol Clin N Am 21 (2007) 273–291

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

Hormonal Therapy for Advanced Breast Cancer Hope S. Rugo, MD Breast Oncology Clinical Trials Program, University of California, San Francisco Comprehensive Cancer Center, 1600 Divisidero Street, 2nd Floor, San Francisco, CA 94115, USA

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locking the effects of estrogen and progesterone in women who have breast cancer continues to be one of the most rapidly advancing areas of research in oncology. Hormonal therapy for advanced breast cancer was the first effective treatment for this disease, dating back more than 100 years and evolving from suppression of ovarian function with surgical oophorectomy [1] or radiation [2] to the current, more highly selective antihormonal therapy options. Additional surgical therapies, such as adrenalectomy and hypophysectomy [3], were replaced several decades ago by tamoxifen [4] and the first-generation aromatase inhibitor aminoglutethimide (AG) [5,6]. The discovery of the estrogen receptor (ER) [7], followed subsequently by data correlating levels of the ER and the progesterone receptor (PgR) with response to various endocrine therapies [8], has greatly improved the ability to target specific tumor biology. Even patients whose tumors express very low levels of ER or PgR may respond to hormone therapy [9]. With the introduction of the highly selective and potent third-generation aromatase inhibitors (AIs) and the estrogen receptor down-regulator (SERD) fulvestrant, options for the treatment of advanced hormone receptor (HR)–positive (HRþ) breast cancer have greatly expanded (Table 1). At the same time, numbers of studies have demonstrated the importance and effectiveness of sequential therapy [10], including selective estrogen receptor modulators (SERMs) and progestational agents, along with high-dose estrogens. This article reviews the use of hormonal therapy in the metastatic setting and discusses the results of recent studies. In addition, current and planned trials combining hormonal therapy with targeted agents with the goal of improving response and overcoming resistance are addressed. SELECTIVE ESTROGEN RESPONSE MODIFIERS The ERs are nuclear proteins called transcription factors. These factors regulate expression of estrogen-responsive genes (including the PgR) and mediate almost all of the effects of estrogen in the nucleus [11] and in the cytoplasm (nongenomic effects). Tamoxifen, a triphenylethylene that was first synthesized E-mail address: [email protected] 0889-8588/07/$ – see front matter doi:10.1016/j.hoc.2007.03.007

ª 2007 Elsevier Inc. All rights reserved. hemonc.theclinics.com

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Table 1 Hormonal treatment of advanced breast cancer Category

Agent

Selective estrogen response modifiers (SERMs)

Tamoxifen Toremifene Fulvestrant DES Estradiol Megestrol acetate Anastrozole Letrozole Exemestane Goserelin Leuprolide Triptorelin

Selective estrogen receptor down-regulator (SERD) Estrogens Progestins Aromatase inhibitors (nonsteroidal) Aromatase inhibitors (steroidal) GnRH agonists

Abbreviation: DES, diethylstilbestrol.

in the 1960s, binds with high affinity to cytoplasmic ER and was the first oral agent demonstrated to be an effective therapy for the treatment of advanced breast cancer. Initial response rates were in the 20% to 40% range in post[12,13] and premenopausal women [14] and greater when cancers known to be HRþ were selected. Based on these impressive response rates and low rate of toxicities compared with diethylstilbestrol (DES) [15], tamoxifen quickly became the first-line treatment of choice for hormone-responsive advanced breast cancer. Initially believed to be an antiestrogen, tamoxifen was subsequently found to have estrogen agonist activity also, including tissue-dependent effects on bone, endometrium, and lipids [16]. Although generally thought of as a disadvantage, it is now clear that the estrogenic effects of tamoxifen may play a useful role in preserving bone mineral density and cardiovascular health and reducing at least some of the gynecologic symptoms associated with estrogen deprivation. This agonist effect also results in toxicities, however, including a small increase in the risk for endometrial cancer, cataracts, thromboembolic disease, ovarian cysts (in premenopausal women), and endometrial polyps, along with short-term side effects, such as hot flashes. Because of its dual effect, tamoxifen and subsequent agents in its class are termed SERMs. Toremifene is another triphenylethylene derivative related to tamoxifen that was developed in an attempt to reduce the toxicity of tamoxifen while maintaining efficacy. Promising data in the Phase I and II settings led to a phase III trial comparing two doses of toremifene to tamoxifen in postmenopausal women who had HR-positive or -unknown metastatic breast cancer [17]. Similar to previous data with tamoxifen, there was no evidence of a dose-response effect for toremifene, and rates of response, time to progression, and toxicity were equivalent between the two SERMs. More than a third of patients had HR-unknown disease; however, response rates were about 20% in all arms, with an additional 25% to 30% of patients experiencing stable disease (SD), defined as no evidence of progression for at least 24 weeks. Tumor flare [18],

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manifested as a transient increase in bone or musculoskeletal pain, hypercalcemia, or an increase in skin lesions within 2 weeks of starting therapy, was seen with both agents. Metabolic flare as evidenced by positron emission tomography has been associated with responsiveness to tamoxifen therapy [19]. Median survival in the phase III trial was 2.5 years in both arms, in contrast to current longer survival rates for HRþ advanced disease [20], emphasizing the significant progress that has been made over the last 2 decades driven by new hormonal and chemotherapeutic options for the treatment of this disease. PROGESTATIONAL AGENTS Oral megestrol acetate (MA) [21,22] and parenteral medroxyprogesterone acetate (MPA) [23] were shown to be effective therapy for postmenopausal women who had hormone-responsive breast cancer in the early 1970s [24]. The antitumor effects are not completely understood, but are believed to be attributable to reduction of the ER and PgR and suppression of adrenal steroid production [25]. Initial studies focused on dose intensity, but over time failed to show an advantage from dose escalation, although toxicity was moderately increased [26]. Comparison studies showed that first-line treatment with tamoxifen or MA resulted in similar response rates and time to progression (TTP), but tamoxifen was associated with less weight gain and fluid retention, although more hot flashes [27,28]. Similar results were found comparing the first-generation nonselective aromatase inhibitor AG to MA, although in this case MA was associated with less toxicity [29]. Based on these studies, the sequencing of hormonal therapy for metastatic breast cancer became tamoxifen, followed by MA, then followed by AG until the advent of the third-generation AIs. AROMATASE INHIBITORS The development of the third-generation AIs has dramatically revolutionized the treatment of women who have HRþ breast cancer [30]. The aromatase enzyme, found in adipose tissue, muscle, liver, and breast, acts at the final step in estrogen synthesis to convert the androgens androstenedione and testosterone to estradiol and estrone, respectively. In the postmenopausal state, these tissues have higher amounts of aromatase and produce estrogen locally. The first-generation AI, AG, was a nonspecific inhibitor of aromatase and treatment was associated with reduced production of mineralocorticoids and glucocorticoids requiring daily replacement of cortisol [31]. Treatment with AG was also associated with significant side effects, including drowsiness and rash. Second-generation AIs were injectable and did not offer an advantage over AG; however, the third-generation inhibitors are oral, highly specific, and potent, inhibiting almost all enzyme activity at the terminal step of estrogen synthesis. These agents can be divided into two categories, steroidal inactivators and nonsteroidal inhibitors, based on chemical structure and mechanism of action. Exemestane has a steroidal structure similar to androstenedione, a naturally occurring substrate of the enzyme, and thus covalently binds to the substrate-binding site to irreversibly inactivate aromatase. Anastrozole and letrozole are nonsteroidal

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reversible inhibitors that interfere with the porphyrin ring of the cytochrome P450 group on the enzyme and impair catalytic function. All three agents result in profound suppression of enzyme activity and consequently circulating and tissue levels of estrogen in postmenopausal women, and the clinical significance of these differences is unclear. The newer AIs were first studied in postmenopausal women who had locally advanced or metastatic disease progressing on or following tamoxifen and each agent was compared to MA. All three drugs were shown to be at least to some degree superior to MA with a more favorable side-effect profile [32–34]. More than 2200 postmenopausal women were randomized on four different trials; two trials comparing anastrozole to MA were pooled for analysis. Exemestane resulted in a significantly longer TTP than MA of 4.7 versus 3.8 months in a study involving 769 patients, and the median overall survival (OS) at last follow-up had not been reached in the exemestane arm [34]. In pooled data from two trials of 561 women, anastrozole was superior to MA in median OS of 26.7 versus 22.7 months [35]. Treatment with letrozole in a trial including 363 women resulted in a significant improvement in the overall response (OR) rate (ORR) compared with MA, at 23.6 versus 16.4 percent [33]. Multiple studies have subsequently shown either equivalency or superior response rates or TTP with third-generation AIs compared with tamoxifen as first-line treatment of advanced disease (Table 2) [36]. The North American and TARGET (European) trials randomized a total of 1021 postmenopausal patients who had newly diagnosed advanced breast cancer, or progressive disease after first-line therapy, to receive either anastrozole or tamoxifen [37,38]. The primary endpoint was time to TTP, with secondary endpoints including objective response and tolerability. Of note, 89% of patients in the North American study were known to have HRþ disease, compared with only 45% of patients in the TARGET study. Preliminary analyses found no difference between the two treatment groups with regard to TTP, ORR, clinical benefit (OR and the number of patients who had SD for at least 24 weeks [CB]), or duration of response [39]. Data analysis after 43.7 months of follow-up showed no significant difference in median time to death [40], with a median survival of Table 2 First-line hormonal treatment of metastatic breast cancer with aromatase inhibitors versus tamoxifen in postmenopausal women

Patients (N) OR (%) CB (%) PFS (mo) ER unknown (%)

Anastrozole [37]

Anastrozole [39]

Letrozole [42]

Exemestane [36]

171 versus 182 21 versus 17 59 versus 46* 11.1 versus 5.6* 11 versus 11

340 versus 328 33 versus 33 56 versus 56 8.2 versus 8.3 56 versus 54

453 versus 454 182 versus 189 32 versus 21* 46 versus 31* 49 versus 38* 66 versus 49* 9.4 versus 6* 9.9 versus 5.8* 34 versus 33 15 versus 11

Abbreviations: CB, clinical benefit, stable disease for >24 weeks plus OR; ER, estrogen receptor; OR, overall response, partial response plus complete response; PFS, median progression-free survival. *Significantly different from tamoxifen.

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39.2 versus 40.1 months for anastrozole group and tamoxifen, respectively. A retrospective analysis of the ER and PRþ subgroup revealed similar results. There were fewer thromboembolic events in the patients receiving anastrozole compared with tamoxifen. Although these data demonstrated non-inferiority of anastrazole, the authors concluded that the AI might be preferentially used in the first-line setting because of its improved side-effect profile. The activity of letrozole in advanced disease was also studied in a large international phase III trial. In the Letrozole 025 study, 916 postmenopausal women who had advanced HRþ breast cancer were randomized to first-line hormonal therapy with either letrozole or tamoxifen [41]. The primary endpoint was TTP, with the secondary endpoints being rate of OR, rate of CB, time to response, OS, and safety. After 32 months of follow-up, women treated with letrozole had a significantly improved TTP (9.4 versus 6 months, hazard ratio 0.72), ORR (32% versus 21%), and CB rate (50% versus 38%). Subgroup analysis demonstrated improved TTP in patients treated with letrozole in patients who had nonvisceral metastases, visceral but not liver metastases, and liver metastases, but these differences were not statistically significant. OS was similar between both groups (34 versus 30 months), although an unplanned retrospective analysis showed improved survival at 1 and 2 years in those patients receiving letrozole [42]. Patients were permitted to cross over to the other study arm at the time of disease progression, so only the early survival data reflect the impact of the initial drug received. Because of the crossover design, this study was also able to demonstrate the impact of sequencing hormonal agents on survival, regardless of the order of therapy (see discussion on sequencing elsewhere in this article). The improved response rates and TTP combined with modest toxicity nonetheless led to the widespread use of AIs as first-line therapy for HRþ advanced breast cancer. Exemestane was the last third-generation AI to be approved by the FDA for the treatment of breast cancer. An initial phase II study evaluated exemestane or tamoxifen in the first-line treatment of HRþ metastatic disease [43]. A total of 122 postmenopausal women were enrolled in this trial, which demonstrated an improvement in ORR (41% versus 17%) and CB (57% versus 42%) with exemestane compared with tamoxifen. This open-label study was then expanded to a phase III trial including a total of 382 patients [44]. At 29 months of median follow-up, treatment with exemestane was associated with a significant improvement in progression-free survival (PFS, 9.9 versus 5.8 months) and tumor response (ORR 46% versus 31%), but no difference in overall survival similar to the other phase III trials. These data led to several additional areas of study. First, and clearly most important, multiple trials were initiated evaluating AIs in the adjuvant setting. Second, the question of appropriate sequencing of hormonal agents in the metastatic setting arose given the lack of survival benefit across all three phase III trials in hormone-naı¨ve advanced disease. This question was further complicated by the availability of fulvestrant, as described elsewhere in this article. One of the benefits of these trials and the AI studies in the adjuvant setting has been an almost worldwide understanding

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that the use of hormone therapy should, in general, be restricted to those tumors that express at least some level of either ER or PgR as determined by immunohistochemical staining [45]. SELECTIVE ESTROGEN RESPONSE DOWN-REGULATORS Fulvestrant, a novel ER antagonist without agonist effects, is the most recent addition to the armamentarium available to treat HRþ advanced breast cancer [46]. The mechanism of action is based on the steroid structure, which is similar to estradiol with the exception of an added long side chain; this allows fulvestrant to compete with estradiol for binding sites on the ER [47]. Binding of fulvestrant to the ER results in degradation and decreased transcription or down-regulation of the receptor. Initial encouraging response rates from a small phase II trial in tamoxifen-refractory advanced breast cancer [48] led to phase III trials comparing monthly intramuscular injections of fulvestrant to anastrozole after disease progression on or following tamoxifen, and a phase III trial comparing fulvestrant to tamoxifen as first-line therapy for metastatic disease. Two trials compared fulvestrant to anastrazole, one in North America [49] and one in Europe, South America, and Australia [50], with a planned combined data analysis. A total of 851 postmenopausal women who had advanced breast cancer were enrolled; nearly all had received prior tamoxifen. There were no significant differences between the two treatment arms with respect to median TTP, ORR, and the rate of CB. In the smaller North American study, treatment with fulvestrant increased the median duration of response by 9 months compared with anastrozole. These disparate findings may be possibly attributed to the lower percentage of patients who had confirmed HRþ disease in the European trial, thereby reducing the number of patients who would be expected to benefit from hormone therapy. Median survival was identical between the two treatments at about 27.5 months [51]. It seemed that fulvestrant had at least equivalent activity compared with anastrozole in the second-line metastatic setting, and based on these results, fulvestrant was approved for the treatment of HRþ locally advanced or metastatic breast cancer in postmenopausal women who have had progression of disease on tamoxifen. In the third phase III trial, 587 postmenopausal women who had untreated advanced breast disease were randomized to receive either fulvestrant or tamoxifen [52]. At 14.5 months of median follow-up, the drugs were found to be equivalent with respect to TTP, ORR, and median duration of response. In a retrospective subset analysis, patients known to have ER- or PgR-positive tumors had a significantly higher response rate with fulvestrant. These results, although providing another and perhaps more tolerable option to tamoxifen therapy, were somewhat disappointing because it was hoped that the lack of agonist effect and degradation of the ER would represent a therapeutic advantage over existing hormonal agents. The time to response for tamoxifen, the AIs, and fulvestrant in the metastatic setting seems to be similar at about 3 months [53]. Pharmacokinetic (PK) data indicate that once-monthly

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dosing of fulvestrant only results in steady-state levels at 3 months, however, possibly prolonging the time to response unacceptably [54]. One recent study evaluated a loading dose of 500 mg of fulvestrant, following by 250 mg day 14 and day 28, followed by standard monthly dosing [55]. PK studies demonstrated that steady-state levels were achieved at 1 month, suggesting that this is a more appropriate and potentially effective method of administration. Many questions remain about the best way to use fulvestrant, and the impact of this agent in premenopausal women who have breast cancer is unknown. There are ongoing trials assessing the benefit of dosing fulvestrant at 500 mg intramuscularly every 4 weeks. The CONFIRM trial is a phase III study randomizing postmenopausal women who have HRþ advanced breast cancer who have had disease progression after one prior hormonal agent to fulvestrant 500 mg or fulvestrant 250 mg every 28 days. The primary endpoint of CONFIRM is TTP. Other trials are evaluating fulvestrant in combination with AIs in an attempt to improve response and overcome resistance by blocking hormone-driven growth at the receptor and hormone production levels. Data on sequencing fulvestrant with the AIs and tamoxifen and novel combinations are reviewed in later discussion. SEQUENTIAL HORMONE THERAPY The primary goals in the treatment of advanced breast cancer are to palliate symptoms and maintain quality of life while prolonging life as long as possible. For this reason, the endpoint of stable disease defined as lack of progression for at least 24 weeks is clinically important for patients and clinicians [56]. Following the success of AIs followed by fulvestrant as treatment of tamoxifen-refractory and -naı¨ve metastatic disease, there was great interest in understanding optimum sequencing and presence or absence of cross-resistance between the nonsteroidal and steroidal AIs. Based on several different trials, it seems that the different classes of hormonal agents are partially non–cross-resistant in hormone sensitive disease, and that a low level of response but clinically relevant levels of CB may be seen from sequential therapy [57]. In a substudy of the TARGET trial (anastrozole versus tamoxifen), 60 patients were formally selected to cross over to the opposite treatment arm at the time of disease progression and were prospectively followed [58]. Data were presented after a median of 66.3 months from initial randomization and 39.5 months from cross-over. Before cross-over treatment, TTP in the anastrozole group was 11.3 months compared with 8.3 months in the tamoxifen-treated patients. After the cross-over, the patients receiving second-line tamoxifen had a TTP of 6.7 months, compared with 5.7 months for the second-line anastrozole group. The median time to second progression was longer in the anastrozole–tamoxifen group as opposed to the tamoxifen–anastrozole group (28.2 versus 19.5 months). A cross-over analysis was also performed in the letrozole 025 study demonstrating similar response rates to second-line treatment (9% versus 7%) and a longer median duration of

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response (35 versus 16 weeks) in the letrozole–tamoxifen arm. Clinical benefit rates were in the 30% range, with duration lasting 12 to 24 weeks. These data suggest that hormone-sensitive tumors retain responsiveness to tamoxifen after progression on a nonsteroidal AI. Partial non–cross-resistance has also been demonstrated in patients treated with an alternative class of AI after progression on either a nonsteroidal or steroidal agent. Treatment with exemestane after either letrozole or anastrozole in one small study resulted in a CB rate of 43.5% with a median TTP of 5.1 months, whereas treatment with either nonsteroidal agent following exemestane resulted in a CB rate of 55.6% and a TTP of 9.3 months [59]. Fulvestrant is effective following treatment with AIs and tamoxifen [60], with CB seen in approximately 30% of patients regardless of prior responsiveness to AI therapy and lasting for a median duration of 3.5 months [61]. A small study conducted by the North Central Cancer Treatment Group in women who had cancer progressing on an AI demonstrated a partial response rate of 14% and a CB rate of 35%; responses seemed to be higher in patients who had not received prior tamoxifen and included patients who had visceral dominant disease [62]. Patients progressing following treatment with fulvestrant also seem to retain sensitivity to subsequent hormone therapy, regardless of initial response [63]. The phase III EFECT trial is the largest study evaluating sequential therapy with an AI compared with fulvestrant (Table 3) [55]. A total of 693 postmenopausal women who had advanced HRþ breast cancer with recurrence or progression following a nonsteroidal AI were randomized to receive either exemestane or a modified loading dose of fulvestrant (see previous section on fulvestrant). Median TTP was identical at 3.7 months in both groups as were the ORRs and rates of CB. The median duration of response was long, ranging from 9.8 to 13.5 months, and CB was seen in up to 29% of patients who had visceral dominant disease regardless of prior response to the nonsteroidal AI. One ongoing study, Southwestern Oncology Group (SWOG) S0266, is comparing the effects of fulvestrant to anastrozole in the first-line setting. These data are particularly useful given the almost universal use of either upfront or sequential AIs in the adjuvant setting and help to direct strategies for

Table 3 Results of EFECT: evaluation of fulvestrant versus exemestane clinical trial [55] Endpoint

Fulvestrant (n ¼ 351)

Exemestane (n ¼ 342)

P value

TTP (mo) OR (%)a CB (%)a Duration of response (mo)

3.7 7.4 32.2 13.5

3.7 6.7 31.5 9.8

0.65 0.74 0.85 —

Abbreviations: CB, clinical benefit, stable disease for >24 weeks plus OR; OR, overall response, partial response plus complete response; TTP, median time to progression. a In the response evaluable population (n ¼ 270 in each arm).

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the treatment of relapsed HRþ disease. MA may also be effective even in the fourth-line setting in very hormone-responsive disease [57]. The approach to treating HRþ advanced breast cancer must take into account the type and extent of adjuvant hormonal therapy, time since last hormonal treatment, and the biologic aggressiveness of the disease. Options should include sequencing of the nonsteroidal AIs letrozole and anastrozole, the steroidal AI exemestane, fulvestrant, tamoxifen, and megestrol acetate [64].

TREATMENT OF PREMENOPAUSAL WOMEN More than 100 years ago, Beatson [1] reported that endocrine ablation by way of oophorectomy resulted in regression of skin metastases in premenopausal women who had advanced breast cancer. Subsequent studies evaluated the use of ovarian irradiation [2], hypophysectomy [3], and adrenalectomy [6] as hormonal treatment of breast cancer. In the mid 1980s, several studies demonstrated similarity in efficacy between surgical oophorectomy and oral tamoxifen [65,66], and between surgical and chemical castration with gonadotropinreleasing hormone analogs (GnRHa) [67]. The combination of ovarian suppression and tamoxifen was best studied in a relatively small trial conducted by the European Organization for Research and Treatment of Cancer [68]. In a threearmed trial, 161 premenopausal women who had mostly HRþ advanced breast cancer were randomized to receive ovarian suppression with GnRHa buserelin, tamoxifen, or both. With a median follow-up of 7.3 years, combined treatment with buserelin and tamoxifen was superior to either buserelin or tamoxifen with a response rate of 48% compared with 34% and 28%, respectively. Most strikingly, overall survival was also significantly improved at 3.7 years compared with 2.5 and 2.9 years (P ¼ .03). A meta-analysis of four randomized trials comparing combined tamoxifen and ovarian suppression to ovarian suppression alone concluded that the combination was superior in the treatment of metastatic HRþ disease [69]. In contrast, few data are available regarding the safety and efficacy of combining ovarian suppression with AIs. AIs should not be used in women who have functioning ovaries because they do not suppress ovarian production of estrogen. In fact, AIs stimulate ovarian function and have been used to promote follicle maturation and egg harvesting for in vitro fertilization [70]. There is great interest in combining AIs with concomitant ovarian suppression using GnRHa in the metastatic and adjuvant settings, however. Preliminary results are available from a small phase II study treating premenopausal women who had recurrent HRþ breast cancer with both the GnRHa goserelin and anastrozole [71]. Estradiol was suppressed to less than 10 pg/mL in all 20 patients, and the majority had a sustainable reduction of estradiol for greater than 6 months. Clinical responses were seen in 7 patients. Caution must be taken in using this combination in premenopausal women until more data are available on efficacy and safety. Given the known effect of AIs on ovarian function, it is important to monitor serum estradiol levels to assure

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effectiveness of the GnRHa. Ongoing studies in the adjuvant setting are evaluating the combination of ovarian suppression with either tamoxifen or AI therapy. ESTROGEN The use of estrogen to treat breast cancer is counterintuitive to the current concept of reducing the synthesis of estrogen or blocking the estrogen receptor. Both historical and recent data support the use of estrogen in this setting. Recent in vitro studies have suggested that tumor cells adapt over time in an estrogen-deprived environment to become exquisitely sensitive to estrogen at low doses, with suppression of tumor cell proliferation [72,73] and apoptosis at higher concentrations [74,75]. High doses of estrogen were commonly used to treat advanced breast cancer before 1981 until randomized trials indicated similar response rates to tamoxifen and with a better side effect profile than to ethinylestradiol [12] or DES [15]. Response rates and time to progression were identical in both studies. Serious side effects, including cholelithiasis and deep venous thrombosis, occurred with ethinylestradiol, and 9 patients out of the 74 (12%) assigned to DES discontinued therapy because of toxicity. An update of the larger DES study (n ¼ 143) [76] demonstrated a possible modest survival benefit for women treated with DES (adjusted P ¼ .039) with median survivals of 3 versus 2.4 years. These data, together with the finding that hormone-sensitive cancers may respond to multiple agents in sequence, and laboratory research elucidating possible mechanisms of hormone resistance and estrogen sensitivity, have led to renewed interest in the therapeutic potential of estrogen in advanced breast cancer [77]. Lonning and colleagues [78] studied 32 women who had heavily pretreated breast cancer; 25% had HR-negative or -unknown disease. Treatment with DES at a dose of 5 mg three times a day resulted in a response rate of 31% (10/32; CR 12%, PR 19%). Median duration of response was almost 1 year at 50 weeks (range 30–124þ). Six patients (19%) ended treatment because of side effects with most stopping within the first 2 weeks. Side effects included bleeding, vaginal discharge, mastalgia, gastrointestinal symptoms, and other systemic side effects, such as lethargy and dizziness. A subsequent retrospective study of 12 women who had metastatic disease and multiple lines of prior hormonal therapy treated with 1 mg/d of ethinyl estradiol reported a PR in 3 (25%), and CB in 4 (33%), with a TTP of 10þ months [79]. Only 1 patient discontinued because of toxicity. Ongoing trials are testing variable doses of different estrogen preparations in hormone-refractory breast cancer, and one group has suggested that the optimal way to avoid hormone resistance might be to alternate antiestrogen and estrogen therapy [80]. Based on these data along with historical experience, the use of higher-dose estrogen as therapy for patients who have highly hormoneresponsive metastatic breast cancer and prior endocrine exposure is an intriguing additional therapeutic option. Toxicity, particularly the increased risk for thrombosis, must be carefully monitored and this treatment should be used with caution and after available less-toxic options have been exhausted. New

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research on mechanisms of endocrine resistance related to altered estrogen dose response has led to current clinical trials testing the incorporation of estrogen in the hormonal treatment approach to advanced disease. RESISTANCE TO HORMONE THERAPY Although patients who have metastatic breast cancer may have an initial clinical response to various hormone agents given in sequence, all patients eventually develop progressive disease and subsequent resistance to further endocrine manipulation. In addition, there is great variety in the extent and duration of response to hormone therapy, even between cancers that seem to be biologically similar. The mechanisms responsible for estrogen-independent growth are an area of intensive study and have led to ongoing and planned clinical trials combining biologic targeted therapy with hormonal agents in an attempt to reverse or overcome resistance [81], and trials combining hormonal agents with different mechanisms of action. At least some degree of resistance to hormone therapy is attributable to loss of ER or PR with the progression of metastatic disease [82]. For this reason, it is useful to obtain biopsies of disease recurrence to ascertain current hormone receptor expression. Resistance to hormone therapy may occur as de novo endocrine resistance, agent-selective resistance, or acquired resistance. A thorough discussion is beyond the scope of this article. Possible mechanisms of resistance to hormone therapy include cross-talk between the ER and growth factor receptor pathways [83] resulting in tumor stimulation even in the presence of ER antagonists. Growth factor signaling seems to activate the ER by phosphorylation and activation of coactivators [84]. Increased expression of several receptors and components of downstream signal transduction pathways have been implicated. Tumor adaptation to very low levels of estrogen can lead to estrogenindependent growth, up-regulation of growth factor receptors, and altered signaling pathways [84]. Probably the best-studied pathway is the HER family of receptors, resulting in several clinical trials combining receptor blockade with hormone therapy in an attempt to improve response and overcome resistance. ROLE OF HER2/NEU OVEREXPRESSION Initial retrospective studies suggested that tumors overexpressing the HER2/ neu receptor were relatively resistant to hormone therapy with tamoxifen [85], and in vitro data demonstrated that overexpression of this family of receptors could potentially stimulate an ER agonist effect of SERMs. This observation led to the hypothesis that aromatase inhibition might overcome this resistance by avoiding receptor-level blockade. Early data from a neoadjuvant trial comparing letrozole to tamoxifen seemed to support this hypothesis [86]; however, subsequent studies have indicated that the presence of HER2/neu receptor overexpression is likely associated with relative resistance to at least most forms of hormone therapy, and that the growth stimulatory effects of the HER2 pathway overcome the effects of therapy directed to the ER. Further

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evaluation of the neoadjuvant trial data indicated no real difference in suppression of proliferation as measured by Ki67 comparing tamoxifen to letrozole in HER2 amplified tumors [87]. Furthermore, evaluation of a subset of 562 patients enrolled in the phase III trial comparing letrozole with tamoxifen found no difference in ORR or rate of CB in patients who had an elevated serum HER2 level 14 days before starting hormonal therapy [88]. Using a cutoff for normal levels of less than 15 ng/mL, patients who had an elevated level at start of therapy had a significantly worse prognosis than those patients who had a normal level. This clear evidence of relative resistance led to several studies combining the antibody to the HER2/neu receptor with AIs, with the hypothesis that hormone sensitivity might be restored with blockade of the growth factor receptor [81,83]. Data from a phase III trial comparing anastrozole to anastrozole with trastuzumab were recently presented and shed further light on this interesting area. The TAnDEM study randomized 207 postmenopausal women who had HRþ and HER2/neu-positive metastatic breast cancer; the primary endpoint was PFS (Table 4) [89]. Indeed, PFS was prolonged in patients receiving the combination therapy (4.8 versus 2.4 months, P ¼ .0016), as was the partial response rate in those who had measurable disease (20.3 versus 6.8 months, P ¼ .018). There was no difference in OS, although an unplanned subset analysis suggested that a possible difference in survival in those patients who did not have liver metastases. The very short PFS seen in patients treated with anastrozole alone in this study clearly supports the concept of relative resistance to hormone therapy for HER2/neu overexpressing disease, despite the use of an AI. Preclinical studies explored the effect of epidermal growth factor receptor (EGFR) blockade in reversing hormone resistance in cell lines with encouraging results [90,91]. It may be that a more complete blockade of the combined EGFR/HER2 pathway is required to reverse hormone resistance [92]. Ongoing trials are evaluating the effect of combining either letrozole or fulvestrant with lapatinib, a dual oral tyrosine kinase inhibitor of the EGFR and HER2/neu, in patients who have HRþ and both HER2/neu-normal and -overexpressing advanced disease. Table 4 Results of the TAnDEM trial [89] Endpoint

Anastrozole (n ¼ 104)

Anastrozole þ trastuzumab (n ¼ 103)

P value

PFS (mo) PR (%) CB (%) OS (mo)a

2.4 6.8 27.9 23.9

4.8 20.3 42.7 28.5

0.0016 0.018 0.026 NS

Abbreviations: CB, clinical benefit in all patients; OS, overall survival; PR, partial response in patients who had measurable disease (n ¼ 73 versus 74). a More than 50% of patients crossed over on progression to receive trastuzumab.

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OTHER GROWTH FACTOR RECEPTORS AND DOWNSTREAM SIGNALING Other growth factor receptors have been implicated in resistance to hormone therapy in HRþ disease. The insulin-like growth factor receptor (IGFR) seems to phosphorylate the ER and may play an important role in receptor cross-talk in the development of hormone resistance [93]. Several IGFR inhibitors are in early clinical trials to investigate this hypothesis. The vascular endothelial growth factor induces proliferation of breast cancer cells, and increased levels of VEGF have been associated with poor response to endocrine therapy [94]. Based on encouraging results from a phase II study [95], a new phase III trial will compare first-line therapy of advanced HRþ breast cancer with an AI to the combination of an AI and inhibition of angiogenesis with bevacizumab, an antibody to VEGF. Inhibition of downstream signaling pathways that activate the ER is another strategy that has been used to reverse hormone resistance [96]. The combination of letrozole with temsirolimus, an inhibitor of a downstream target termed mammalian target of rapamycin (mTOR), was tested in a phase III trial compared with letrozole alone in the treatment of metastatic breast cancer. This trial, which enrolled more than 1000 patients, was closed early because of lack of superiority of the experimental arm [97]. An ongoing neoadjuvant study is evaluating specific phenotypes that might predict response to the combination of letrozole and another mTOR inhibitor, everolimus [98]. The combination of targeted biologic therapy and hormone therapy is being tested in many ongoing and planned trials [81,96]; future studies need to focus on identifying resistant tumor phenotypes and identifying specific pathways that drive tumor growth in an individual tumor. OTHER MECHANISMS OF RESISTANCE Host factors determine the metabolism of anticancer agents, therefore potentially affecting efficacy and toxicity. Recent data suggest that polymorphisms of the Cyp2D6 pathway may impact the therapeutic efficacy of tamoxifen by altering metabolism to its active metabolite, endoxifen [99]. A small percentage of the population are slow metabolizers, whereas other phenotypes are associated with much more rapid metabolism. A recent retrospective study suggests that people who have slow metabolizing phenotypes may derive much less benefit from tamoxifen in the adjuvant setting. If confirmed in prospective studies, this information could be used to individualize hormone therapy to alternate agents in patients who have slower metabolism of tamoxifen. SUMMARY There are now multiple hormonal agents with demonstrated efficacy in the treatment of advanced HRþ breast cancer that have significantly broadened the treatment options for women who have this disease. Three highly specific and potent inhibitors of the aromatase enzyme are now approved for the treatment of postmenopausal metastatic and early-stage breast cancer and offer improved efficacy and a different side-effect profile. The SERD fulvestrant has

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been shown to be as effective as anastrozole in tamoxifen-resistant disease, an alternative to tamoxifen as first-line therapy, and equivalent to the steroidal AI exemestane in disease progressing on nonsteroidal AIs. Recent data have clarified an improved dosing schedule for this injectable agent. These hormonal therapies may be used in sequence depending on adjuvant therapy and prior response to treatment with significant clinical benefit. Older agents, such as megestrol acetate and estrogens, may also be used effectively in the treatment of metastatic hormone-sensitive disease, although use is usually relegated to the fourth- and fifth-line setting. Studies are ongoing to better understand how to use the newer hormonal agents in premenopausal women; current data suggest that the combination of ovarian suppression and tamoxifen may be superior to either agent used alone. Understanding and reversing resistance to hormonal therapy is the subject of intense research in the preclinical and clinical arena. A recently reported trial has helped to further the understanding of hormone resistance in HER2/neu-overexpressing disease. Multiple ongoing or planned trials are evaluating combinations of targeted biologic therapy and hormonal agents. References [1] Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1869;2:104–7. [2] Schinzinger A. Ueber carcinoma mammae. Verh Dtsch Ges Chri 1889;18:28–9. [3] VanGilder JC, Goldenberg IS. Hypophysectomy in metastatic breast cancer. Arch Surg 1975;110(3):293–5. [4] Gale KE, et al. Hormonal treatment for metastatic breast cancer. An Eastern Cooperative Oncology Group Phase III trial comparing aminoglutethimide to tamoxifen. Cancer 1994;73(2):354–61. [5] Harvey HA, et al. A comparative trial of transsphenoidal hypophysectomy and estrogen suppression with aminoglutethimide in advanced breast cancer. Cancer 1979;43(6): 2207–14. [6] Santen RJ, et al. A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med 1981; 305(10):545–51. [7] Jensen EV, et al. Estrogen-receptor interactions in target tissues. Arch Anat Microsc Morphol Exp 1967;56(3):547–69. [8] Osborne CK, et al. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 1980;46(Suppl 12):2884–8. [9] Yamashita H, et al. Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer. Breast Cancer 2006;13(1): 74–83. [10] Carlson RW, Henderson IC. Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole. Breast Cancer Res Treat 2003;80(Suppl 1):S19–26 [discussion: S27–8]. [11] Osborne CK, Zhao H, Fuqua SA. Selective estrogen receptor modulators: structure, function, and clinical use. J Clin Oncol 2000;18(17):3172–86. [12] Beex L, et al. Tamoxifen versus ethinyl estradiol in the treatment of postmenopausal women with advanced breast cancer. Cancer Treat Rep 1981;65(3–4):179–85. [13] Ward HW. Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J 1973;1(5844):13–4.

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