Current Status of Endocrine Therapy for Metastatic Breast Cancer

Hormonal manipulation is currently the mainstay of palliative care for metastatic breast cancer because it is well tolerated and produces significant responses in approximately one-third of unselected patients. Tamoxifen, a nonsteroidal antiestrogen, is currently considered first-line therapy. Second-line agents include progestins and aromatase inhibitors. New agents, such as the "pure" antiestrogens and the gonadotropin-releasing hormone (GnRH) agonists, are being tested. Other approaches for affecting the hormonal milieu are also under investigation, including combinations of hormonal agents, hormonal agents plus biologics, and hormonal agents plus antiproliferative agents. This review will address the basis for endocrine therapy and possible mechanisms of hormonal resistance, currently available agents and newer ones on the horizon, and areas of future interest.

Introduction

Breast cancer, the most common neoplasm in American women, will result in approximately 46,000 deaths in 1995 and is second only to lung cancer as a cause of cancer-related mortality in women [1]. At diagnosis, approximately 5% of women have metastatic disease, and current treatment for these women is only palliative. Consequently, it is important to define new therapeutic modalities and refine the therapeutic index of those already being used.

This paper reviews (1) the basis of endocrine therapy, a well-accepted treatment for metastatic breast cancer, (2) currently available and newer hormonal agents, (3) areas now under investigation, and (4) mechanisms of hormonal resistance.

Endocrine therapy generally is well tolerated by women with metastatic breast cancer and elicits a response in approximately one-third of unselected patients and in at least 50% of patients whose tumors are estrogen-receptor (ER) positive. Well-defined factors associated with a greater likelihood of response to endocrine therapy include:

• ER- and progesterone-receptor (PR) positivity
• Late premenopausal or late post-menopausal status
• Older age
• Long interval from diagnosis to first recurrence (disease-free interval)
• Disease limited to sites outside the viscera, such as bone and soft tissue
• Previous response to endocrine therapy [2].

Because of their favorable therapeutic index, hormonal agents are the treatment of choice for asymptomatic patients with metastatic breast cancer, especially those who are older. Randomized trials show no adverse effect on survival for patients initially treated with endocrine therapy rather than chemotherapy, although initial rates of response to chemotherapy tend to be somewhat higher [2-4]. Tamoxifen has been the drug of choice for first-line treatment of advanced disease because of its low toxicity. Second-line therapy now includes progestins and aromatase inhibitors, which have response rates similar to tamoxifen but more side effects (Tables 1 and 2).

Possible Mechanisms of Hormonal Manipulation

Breast cancer cells have steroid receptors for estrogens, progestins, glucocorticoids, and androgens. Treatment of breast cancer in premenopausal women traditionally has involved removal of the ovaries, the source of estrogen, and, in postmenopausal patients, administration of pharmacologic doses of estrogen. (In postmenopausal women, large doses of estrogen can cause tumor regression.) The exact mechanism of these treatment modalities and the effects of estrogens and antiestrogens on the breast cancer cell are not fully defined. Our current understanding is that estrogen downregulates ERs and thereby decreases the hormone's effects [14].

Heat Shock Proteins--One speculative mechanism involves heat-shock proteins (hsps). When an estrogen antagonist (E) interacts with the ER, the ER-hsp complex dissociates. The DNA-binding domain then attaches to the estrogen-binding site on the DNA, initiating transcription of estrogen-regulated genes. Conversely, binding of an antiestrogen (AE) to the ER stabilizes the DNA-hsp, which prevents the ER-DNA interaction and thereby inhibits transcription (Figure 1).

Growth Factors--Breast cancer cells also secrete other growth factors that are autostimulatory (autocrine) and/or are stimulated by substances secreted by surrounding cells (paracrine; see Figure 2). Receptors for epidermal growth factor (EGFRs) and a closely related gene product, c-erbB2 (Her-2/neu), are found on breast cancer cells. Epidermal growth factor and transforming growth factor-alpha (TGF-alpha) interact with the EGFR and activate tyrosine kinase, a signal transduction pathway shown to induce proliferation of breast cancer cell lines in nude mice [15].

Transforming growth factor-alpha can act as an autocrine or paracrine growth factor. Receptors for TGF-beta also are present on breast cancer cells (primarily those that are ER-negative), and some breast cancer cells produce TGF-alpha in response to estrogens. Using antibodies against TGF-alpha or EGFR to block the effects of TGF-alpha can inhibit some breast cancer cells.

Insulin-like growth factor (IGF) also is produced by breast cancer cells in vitro and may result in both autocrine and paracrine mitogenic effects [16]. Factors that increase IGF production include estrogen, TGF-alpha, EGF, and insulin. Antiestrogens, TGF-beta, and glucocorticoids inhibit its secretion [15].

Currently Available Hormonal Therapies

Currently available additive therapies include androgens, progestins, gonadotropin-releasing hormone (GnRH) agonists, corticosteroids, and, paradoxically, estrogens. Androgens, which were discovered to be effective in the 1940s, cause breast cancers to regress in approximately 20% of patients but are poorly tolerated because of virilization and other major toxicities.

Physiologic doses of estrogen (hormone replacement therapy) are generally avoided in women with breast cancer because of theoretical concerns that they might stimulate breast cancer cell growth. Higher doses yield response rates in postmenopausal women similar to those produced by other available agents, but estrogen therapy is frequently associated with nausea, vomiting, and other toxic effects [17,18]. During the 1950s, progestins were found to yield response rates of 30% in unselected patients with breast cancer [19].

Response rates of 20% to 25% also were reported for corticosteroid therapy alone [20]. For example, in elderly patients in whom endocrine therapy has failed, 15 mg of prednisolone administered daily caused tumor regression in 14% of patients and tumor stabilization lasting 6 months or longer in 21% [21]. Corticosteroids also can improve sense of well being, appetite, and functional status in seriously ill cancer patients [22]. However, because of their long-term undesirable toxicities, corticosteroids typically are reserved for reducing inflammation and swelling in patients with intracranial metastases or the superior vena cava syndrome.

Gonadotropin-releasing hormone agonists have proven effective in pre-menopausal patients with metastatic breast cancer, but their role in standard practice has not yet been defined.

Tamoxifen, the prototypic hormonal agent used in breast cancer, is one of several antiestrogens now available and falls into the broad category of hormone antagonists. Other groups of hormone antagonists only recently introduced into the breast cancer treatment armamentarium include antiprogestins, antiandrogens, and aromatase inhibitors.

Antiestrogens

Antiestrogens inhibit the growth of hormone-responsive human breast cancer cells in vitro, an effect modulated through the ER (Figure 1)[23]. Antiestrogens that are currently available or under investigation are listed in Table 3.

Like most antiestrogens, tamoxifen has both estrogen-agonist and estrogen-antagonist effects. Some newer antiestrogens with fewer agonist properties than tamoxifen, and therefore proportionately greater antiestrogenic activity, theoretically should be more effective in ablating the mitogenic action of estrogens on breast tumor growth. "Pure" antiestrogens might also work faster and longer than antiestrogens with partial agonist action and should be less detrimental to other tissues, such as the uterus and liver. Moreover, the concentrations of pure antiestrogen needed to block the ERs in breast cancer cells might not effect ERs in the central nervous system, leading to fewer vasomotor symptoms. Use of pure antiestrogens might also avoid the increase in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and circulating estrogen frequently noted in premenopausal patients using tamoxifen [24].

Tamoxifen

The most popular and effective endocrine treatment currently available for advanced breast cancer, tamoxifen is appropriate initial endocrine treatment in both premenopausal and postmenopausal patients [20,25-27]. As initial therapy, tamoxifen elicits complete and partial responses in 30% to 40% of unselected patients, with response durations averaging about 1 year. Half of patients with ER-positive breast tumors respond [27]. Withdrawing therapy also yields responses in as many as 20% of patients whose tumors initially regressed and later progressed on tamoxifen [28].

Mechanisms of Resistance--Tamoxifen competitively binds to ERs, blocking estrogen binding and inhibiting estrogen-dependent cell growth [29]. Eventually, however, cells develop resistance to tamoxifen. Several mechanisms have been postulated for this: (1) alterations in tumor and cellular heterogeneity; (2) modifications in ER structure and function; (3) changes in paracrine interactions; and (4) pharmacologic alterations in cellular uptake, retention, and/or metabolism [30].

One possible mechanism of tamoxifen resistance was examined by Pommier et al, who serially measured serum estrone (E1), estradiol (E2), and dehydroepiandrosterone (DHEA) in 15 postmenopausal women with ER-positive metastatic breast cancer whose tumors progressed during tamoxifen therapy [31]. Levels of all three steroids increased when the tumor progressed but subsequently decreased after tamoxifen was discontinued.These researchers concluded that tamoxifen stimulates adrenal production of DHEA, which then converts to E1 and E2 via aromatization. When tamoxifen is discontinued, El and E2 production slows, resulting in decreased tumor progression.

Tamoxifen readministration after endocrine ablation via hypophysectomy or oophorectomy (but not adrenalectomy) stimulated increases in serum levels of DHEA, El, and E2. This indicates that the adrenal gland is the source of these sex steroids in postmenopausal women.

Tamoxifen exists in both trans- and cis-configurations [29]. The trans-isomer, available commercially as tamoxifen citrate, is a potent antiestrogen; the cis-isomer is estrogenic. In humans, tamoxifen is metabolized by N-desmethylation and 4-hydroxylation. Trans-4-hydroxytamoxifen, although a minor metabolite, has a higher affinity for the ER and is a more potent antiestrogen than the parent compound, but can isomerize to cis-4-hydroxytamoxifen, which is a less potent antiestrogen with weak estrogenic properties [32].

Isomerization may occur in vivo [33,34]. Osborne and colleagues showed that tamoxifen-resistant human breast cancer cells had lower tamoxifen concentrations and contained higher levels of the less antiestrogenic cis-isomer of 4-hydroxytamoxifen [35]. This suggests that tumor resistance may be related, in part, to the decreased cellular uptake of tamoxifen or conversion of tamoxifen to a less antiestrogenic metabolite. A recent study confirmed that breast cancer cells can metabolize tamoxifen to the more estrogenic compounds [36], but other investigations have been unable to confirm this hypothesis in vitro [37].

Resistance also may result from a mutation in the ER. Karnik and colleagues found genetic changes that could result in mutated receptors in only 2 of 20 tamoxifen-resistant tumors, however [38]. Such mutations, therefore, probably are rare and are unlikely to be a major factor in tamoxifen resistance.

Tumor "Flare"--In approximately 5% of patients with skin or bone metastases, tamoxifen causes a tumor "flare," manifested by an increase in the size, number, and discomfort of skin lesions and by worsening bone pain and/or hypercalcemia. Such reactions generally occur within days or weeks of treatment initiation [39,40]. Flare reactions may develop in association with other hormonal therapies, such as estrogens, androgens, progestins, and ablative therapies [39].

Trioxifene Mesylate

Other antiestrogens with less estrogenic activity than tamoxifen have been evaluated. Clinical studies show that trioxifene mesylate, a potent antiestrogen with low intrinsic estrogenic activity and a higher affinity for the ER than tamoxifen, has antitumor effects comparable to those of tamoxifen. However, further study of this agent has been abandoned because of unacceptable toxicity [41-43].

Toremifene

A triphenylethylene antiestrogen, toremifene has an antiestrogenic/estrogenic ratio five times greater than that of tamoxifen. It is well absorbed after oral dosing, and its elimination half-life is about 5 to 6 days [44,45].

Phase I clinical trials in healthy postmenopausal women showed antiestrogenic activity at daily doses of 20, 40, and 60 mg of toremifene but not 10 mg. Side effects occurred with the same frequency as with tamoxifen. Rarely, dizziness, tremor, hypercalcemia, and allergic reactions were encountered [45]. Phase II trials showed toremifene to be effective and safe for treating post-menopausal women with advanced ER-positive breast cancer [46]. However, more recent trials have found toremifene and tamoxifen to be similar in efficacy and, in fact, to exhibit cross-resistance [47,48].

Other Antiestrogens

Several other antiestrogens have undergone limited clinical testing, including droloxifene (4-hydroxytamoxifen), idoxifene (pyrrolidine-4-iodotamoxifen), and zindoxifene.

Droloxifene--Of these, droloxifene has the most promise. It is less estrogenic and more antiestrogenic than tamoxifen and has been shown to inhibit breast cancer cell growth in vitro and in vivo [49]. Phase I and II studies of droloxifene in ER-positive postmenopausal patients with metastatic breast cancer have demonstrated overall response rates of 30% to 40% with minimal toxicity [50-53]. In patients who have been treated previously with tamoxifen, the response rate is 15% [54]. Larger clinical trials of this agent are underway.

Zindoxifene, an indole derivative of tamoxifen, has shown only marginal therapeutic activity [55].

Idoxifene, when compared to tamoxifen, was found to have a greater affinity for the ER, less estrogenic effect, and greater activity in vitro [56]. Idoxifene is currently under clinical investigation.

Pure Antiestrogens

Two pure antiestrogens have recently been introduced: ICI 164,384 [N-n butyl-N-methyl-11-(3,17-beta-dihydroxyestra-1,3,5(10)-triene-7-alpha-yl)undecanamide] and ICI 182,780 [7-alpha-(9-(4,4,5,5,5-pentafluoro-pentyl sulfinyl)nonyl)estra-1,3,5(10)-triene-3,17-beta-diol].

ICI 164,384 is a novel 7-alpha-analog of 17-beta-estradiol that completely inhibits endogenous and exogenous estrogens and produces castration-like effects on adult rats without affecting the hypothalamic-pituitary-ovarian axis [57]. When studied in human breast cancer cell lines in vitro, ICI 164,384 was 100 times more potent than tamoxifen without the growth stimulatory effect [58-60].

In addition, ICI 164,384 appears to be associated with less resistance, suggesting that it may be more effective than tamoxifen in breast cancer [61]. In fact, ICI 164,384 inhibits tamoxifen-stimulated breast tumor growth.62

ICI 182,780 is substantially more potent than ICI 164,384 [63]. Its oral bioavailability is low, however, and depot formulations are being tested.

One study of ICI 182,780 found that tumor growth ceased for at least 1 month after a single injection [64]. In a trial of postmenopausal women with primary breast cancer, short-term administration of ICI 182,780 was well tolerated and produced demonstrable antiestrogenic effects in breast tumors in vivo without showing any estrogen-agonistic activity [65].

Future trials will test these agents in patients who fail to respond to tamoxifen. Comparisons of pure antiestrogens and tamoxifen are also of interest.

Antiprogestins

Mifepristone (RU 486), the only antiprogestin currently in clinical trials, also has antiglucocorticoid activity, which can result in adrenal insufficiency. A study in 11 postmenopausal women with breast cancer showed an objective response in 1 patient, stable tumors in 6 patients, and progressive disease in 4 patients [66]. Because treatment resulted in increased plasma estradiol levels, mifepristone combined with an antiestrogen or a GnRH agonist may be more successful. Major side effects of mifepristone are related to its antiglucocorticoid properties.

Other progesterone antagonists are under investigation in mammary tumor models. Onaprostone (ZK 98,299) and ZK 112993, for example, have less antiglucocorticoid activity than mifepristone [66,67]. In hormone-dependent rat mammary tumors, these antiprogestins have shown some promise. In previous studies, gestrinone, another antiprogestin, exhibited no antitumor activity in endocrine-sensitive breast cancer [68].

Antiandrogens

Antiandrogens such as flutamide (Eulexin) and cyproterone acetate (Androcur) have undergone only limited investigation in breast cancer. Using 750 mg of flutamide daily, Perrault and colleagues noted only 1 response in 29 women with advanced breast cancer [69]. Most patients had ER-negative tumors and/or received prior hormonal therapy, lowering their likelihood of responding to antiandrogen therapy.

Aromatase Inhibitors

Extraovarian conversion of adrenal androstenedione to estrone is the primary source of estrogen production in postmenopausal women. Aromatase, concentrated mainly in the adipose tissue, muscle, and liver, is the major enzyme involved in this conversion (Figure 3) [70-72]. Table 4 lists the aromatase inhibitors currently in clinical trials.

Aminoglutethimide

By blocking cholesterol side-chain cleavage, 11-beta-hydroxylase, and aromatase, aminoglutethimide (Cytadren) causes medical adrenalectomy and effectively eliminates estrogen production in postmenopausal women [73]. Many studies have confirmed its effectiveness in metastatic breast cancer in this population [20,70-72].

Randomized trials have confirmed that response rates to aminoglutethimide are similar to tamoxifen [27,70]. (Few responses have been observed in pre-menopausal women ) [74]. When given to 120 patients as a second-line therapy after failure of tamoxifen in one study, aminoglutethimide had an overall response rate of 34% with a median response duration of 9.5 months [75]. Twenty-five percent of patients whose tumors failed to respond to tamoxifen responded to aminoglutethimide.

Toxic Effects--Aminoglutethi-mide's major toxicities are lethargy (occurring in 36% of patients), a transient maculopapular rash (25%), dizziness (15%), and nausea and vomiting (10%), with severe myelosuppression reported in less than 1% of patients [76]. The severity and frequency of these side effects have made aminoglutethimide less desirable than tamoxifen or progestins for palliation [72].

Steroid supplementation with hydrocortisone generally is used to prevent the hypoadrenalism that can arise with the standard aminoglutethimide dose of 250 mg four times daily. Randomized trials have shown that lower doses-250 mg twice daily-are as effective as higher doses and can be given without steroid supplementation [27].

Pyridoglutethimide

Formed by aminoglutethimide modification, pyridoglutethimide [pyridyl glutarimide-3-ethyl-3-(4 pyridyl)piperidine-2,6-dione] inhibits aromatase to a similar extent as aminoglutethimide but, unlike that drug, does not inhibit cholesterol side-chain cleavage [77]. Pyridoglutethimide was shown to suppress plasma estradiol concentrations in postmenopausal women with breast cancer [78].

Other Steroidal Aromatase Inhibitors

Other steroidal aromatase inhibitors under study include trilostane (Modrastane), and 4-hydroxyandrostenedione. Other drugs of this class that seem worthy of clinical investigation include testololactone (Teslac), atamestane, 1-methyl-1,4-androstadiene-3,7-dione (MAD), and exemestane.

Trilostane, an inhibitor of 3-beta-hydroxysteroid-dehydrogenase-isomerase, also inhibits aromatase with low potency [79]. Because of its inherent suppression of cortisol synthesis, trilostane must be administered with a glucocorticoid, and its use has been supplanted by other drugs.

4-Hydroxyandrostenedione--Another agent, 4-hydroxyandrostenedione binds irreversibly to and inhibits aromatase in vivo. It is more potent than aminoglutethimide in vitro [80]. Phase II trials in women with advanced breast cancer have shown objective response rates to 4-hydroxyandrostenedione ranging from 23% to 39% and stabilization of disease in 14% to 29% of patients [81-83].

Intramuscular depot forms of 4-hydroxyandrostenedione are being tested in phase III trials. Oral preparations, however, are still in the early stages of development.

Generally, 4-hydroxyandrostenedione has been better tolerated than aminoglutethimide. Side effects of 4-hydroxyandrostenedione include pain at the injection site, hot flashes, lethargy, rash, transient leukopenia, facial swelling, and, rarely, anaphylaxis [84].

Imidazoles

Another class of aromatase inhibitors, imidazoles, also have been shown to decrease estrogen synthesis. This class includes ketoconazole, CGS 16949A (fadrozole), CGS 20,267, and R 83842 (vorozole).

Fadrozole, a tetrahydroimidazopyridine, is a nonsteroidal competitive inhibitor of aromatase that prevents conversion of testosterone to estradiol and androstenedione to estrone. In one phase I trial, fadrozole was 500 times more potent than aminoglutethimide and had minimal toxicity [85]. It is readily absorbed after oral dosing and can be given twice daily.

In clinical studies, fadrazole achieved response rates of approximately 20% in postmenopausal patients with advanced breast cancer [86,87]. Toxicity included hot flashes, nausea and vomiting, fatigue, and loss of appetite.

CGS 20,267 is a nonsteroidal aromatase inhibitor that has the advantage of inhibiting estrogen synthesis but not adrenal steroidogenesis when used at low doses [88]. In phase I trials, it was well tolerated and significantly suppressed estrogen synthesis [89].

Vorozole is a powerful stereospecific inhibitor of the cytochrome P450-dependent aromatase enzyme. Phase II trials recently reported response rates of 25% to 35% when this agent was used as second-line therapy after tamoxifen failure [90-92].

Newer Hormone Agonists

Androgens

Use of androgenic agents, such as testosterone, fluoxymesterone, testolactone, and calusterone, in metastatic breast cancer is associated with response rates in the range of 20% [27]. However, unacceptable side effects occur in many patients; 60% to 70% of patients note masculinization, with deepening of the voice and hirsutism, and 20% to 40% develop hair loss, acne, and increased libido [20]. Tumor flare and hypercalcemia are also encountered more frequently than with other hormonal agents [39]. An effective androgen that has no masculinizing effects has not been found [93,94].

Danazol (Danocrine), a weak androgen with no primary estrogenic or progestational action, also inhibits pituitary gonadotropin secretion and has weak antiprogestogenic activity [95]. Its use as second-line hormonal therapy in advanced breast cancer is associated with response rates of approximately 25% [96-99].

Coombes and colleagues noted responses in 17% of 41 postmeno-pausal women with advanced breast cancer treated with the drug [96]. No responses were seen in premenopausal patients. Toxicities, which occurred in 22% of patients, included lethargy, peripheral edema, and hot flashes. Generally mild, these side effects decreased when the dose was lowered; no patient discontinued therapy due to toxicity.

Response to danazol in other studies has not been as promising. Pronzato and colleagues claimed responses in only 3 of 21 patients, and Brodovsky and coworkers reported only 2 partial responses in 35 postmenopausal women [98,99]. A later study by Coombes and colleagues found responses in only 10 (14.9%) of 69 patients with advanced breast cancer [97]. Low toxicity may make danazol a viable salvage agent although response rates may be low.

Progestins

Progestational agents have been shown to abrogate the trophic effects of estrogen [15]. Response rates of 20% to 40% have been achieved with progestins, and randomized trials have shown that progestins are equal in efficacy to tamoxifen and other endocrine agents [100-103]. When given in standard doses, progestins have minimal toxicity. Weight gain is the only significant consideration with long-term use.

Progestational agents currently available include medroxyprogesterone acetate (Depo-Provera) and megestrol acetate (Megace).

Medroxyprogesterone--Phase II trials have shown high doses of medroxyprogesterone to be superior to lower doses. However, randomized trials have been inconclusive, and it is unclear whether progestins have a dose-response effect [104-109].

Megestrol, an orally administered agent, is the progestin most often used in the treatment of metastatic breast cancer in the United States [110]. Serum levels achieved with oral megestrol doses of 160 mg/d are similar to those attained with medroxyprogesterone doses of 1,000 mg/d. In one randomized trial, 160 mg of megestrol daily produced a higher response rate than 800 mg but no convincing improvement in survival [111]. Preliminary results from a similar Cancer and Leukemia Group B trial have not confirmed these observations.

High doses of progestins may be more effective than lower doses or tamoxifen in causing regression of bone metastases [111,112].

Gonadotropin-Releasing Factors

Gonadotropin analogs cause pituitary-gonadal axis suppression similar to surgical or radiotherapeutic castration but without serious side effects. In 1976, DeSombre and colleagues demonstrated that rat mammary tumors could be reduced by a luteinizing-hormone releasing-hormone (LH-RH) analog [113]. Since then, a series of experimental studies in rodents has defined the effects of chronic LH-RH agonist treatment at pharmacologic doses: (1) decreased gonadotropin and prolactin secretion; (2) a striking fall in plasma sex steroids preceding a reduction in weight of accessory sex organs; (3) inhibition of enzymes involved in steroidogenesis; and (4) direct effects on extrapituitary tissues, such as breast tumor cells [114].

Pituitary gonadotropin secretion is dependent on the intermittent, pulsating secretion of GnRH by the hypothalamic neurons (Figure 4) [115]. Continuous stimulation of the pituitary by GnRH or the long-acting GnRH agonists results in desensitization of gonadotropin secretion and subsequent gonadal suppression [116].

Clinical Effects--The clinical utility of the GnRH analogs in premenopausal women rests on its continuous stimulation. GnRH analogs bind to the GnRH receptors in the pituitary with an affinity ten times that of natural GnRH and block the effects of normal hypothalamic GnRH. This results in long-term inhibition of FSH and LH secretion and estrogen suppression in premenopausal women [114]. In post-menopausal women, LH and FSH levels are suppressed, but estrogen levels remain relatively unchanged, accounting for the limited clinical effect of GnRH analogs in postmenopausal patients [117].

Gonadotropin releasing-hormone analogs may also have a direct anti-tumor effect. Low-affinity binding sites for GnRH have been demonstrated on human breast cancer cells; invitro, growth of these cells is inhibited in the presence of GnRH agonists [118,119].

Formulations--Table 5 lists the GnRH analogs currently in clinical trials. Because LH-RH analogs are small peptides susceptible to digestion in the gastrointestinal tract, they are unsuitable for oral use and must be administered via nasal spray or subcutaneous or intramuscular injections. Newly available depot forms offer greater efficacy and ease of administration.

Toxic Effects--Gonadotropin releasing-hormone analogs cause hypogonadism, and their side effects include hot flashes (usually transient), decreased libido, and depression. Interestingly, tumor flare has not yet been described with these agents [6].

Phase II Trials--Results of phase II studies with GnRH analogs in pre-menopausal women have been encouraging. Response rates have approximated 40%, with little variation noted among different agents [114]. Patients with ER-positive tumors had an objective response rate of 50%, whereas those with receptor-negative tumors responded less frequently (7% to 33%) [120]. Response duration has been approximately 1 year.

Combination Endocrine Therapy

Investigational approaches for affecting the hormonal milieu include (1) combinations of hormonal agents, (2) hormonal agents and biologics, and (3) hormonal and antiproliferative agents (for example, fenretinide).

Hormonal Agent Combinations

Theoretically, hormonal agent combinations may further reduce estrogen levels and/or decrease the effects of estrogen on breast cancer cells. To date, however, no hormonal agent combination has been shown to be convincingly superior to single-agent therapy. Some trials have shown higher response rates, but longer survival or response duration generally has not been seen [27,121]. In other trials, the toxicity of combination regimens was prohibitive [122-124].

Hormonal Agents Plus Biologics

Interferon-alfa increases ER expression and potentiates tamoxifen inhibition of breast cancer cell growth in vitro [125]. In vivo studies of this combination have shown complex effects, however, and clinical trials have been inconclusive [126].

Hormonal Plus Antiproliferative Agents

Fenretinide, a vitamin A analog, displays chemopreventive properties against carcinogen-induced mammary cancer in rodents. Combined with tamoxifen, it recently was tested in women with metastatic breast cancer [127]. In 12 of 15 patients, disease improved or stabilized, and side effects were minimal. Phase III trials are being designed.

There is evidence that the combination of somatostatin (Zecnil) plus tamoxifen leads to decreased levels of IGF-1. Clinical trials of this combination are underway.

Current Stepwise Approach to Endocrine Therapy

Premenopausal, ER-positive Women

1. Tamoxifen--Tamoxifen is as efficacious as oophorectomy and has low toxicity, relatively low cost, and is easy to administer.

2.Surgical or Radiotherapeutic Oophorectomy or GnRH Analogs--Surgical or radiotherapauetic oophorectomy and GnRH analogs are associated with response rates of 30% to 40%. These therapies have more potential toxicities than does tamoxifen and, therefore, should be reserved for second-line therapy.

3. Progestins (such as megestrol acetate)--Megestrol acetate yields similar response rates to tamoxifen but has greater toxicity. Therefore, it is chosen as third-line therapy.

Postmenopausal, ER-Positive or ER-Negative Women

1. Tamoxifen--Because of its low toxicity and ability to elicit tumor regression in 30% to 40% of unselected patients, with responses lasting up to 1 year, tamoxifen is considered first-line endocrine therapy in women with metastatic breast cancer.

2.Progestins (Such as Megestrol Acetate)--Megesterol has a toxicity profile intermediate between tamoxifen and aminoglutethimide and is thus the drug of second choice, although responses to the three drugs are similar.

3.Aromatase Inhibitor (Aminoglutethimide)--Aminoglutethimide is the most toxic of these first three suggested endocrine treatments and, therefore, is recommended as third-line therapy.

4. Estrogens--Estrogens are equal in efficacy to the above agents but have greater toxicity. They should be considered for patients who have done well on prior endocrine therapies.

5. Androgens and Corticosteroids--These agents are probably not as effective as the agents above but do offer another option for endocrine therapy. They may be associated with substantial long-term toxicity.

Progression After Response or Disease Stabilization

In patients who have had a good response or prolonged period of stable disease but who subsequently progress, it is appropriate to discontinue endocrine therapy and observe for a withdrawal response. These responses may last several months or longer.

Change of Therapy/ Entry Into Clinical Trials

Change of therapy is based on disease progression or toxicity. At any point in the algorithm, entry of patients into locally available clinical trials evaluating newer endocrine agents (as previously discussed) should be considered. Patients whose disease is rapidly progressing or immediately life-threatening should be considered for treatment with chemotherapy at any of the steps in this algorithm.

Summary

Endocrine agents represent a mainstay of effective, minimally toxic, palliative treatment for metastatic breast cancer. Current research focusing on the mechanism of action of endocrine agents should provide new insights that should lead to improved therapy.

Ongoing trials of endocrine therapy in metastatic breast cancer are summarized in Table 6; these were obtained from the Physician's Data Query (PDQ) System of the NCI [128]. Development of new agents, especially the pure antiestrogens, is of great interest. Combining endocrine therapy with biologics, especially antiproliferative agents, may lead to more effective treatment in the adjuvant as well as the advanced setting.

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